Medical Policy
Subject: Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling
Document #: GENE.00052Publish Date: 09/28/2022
Status: RevisedLast Review Date: 02/17/2022
Description/Scope

This document addresses gene panel testing (for the purposes of this document, a gene panel is defined by five or more genes or gene variants tested on the same day on the same member by the same rendering provider), whole genome sequencing, whole exome sequencing, molecular profiling (also called comprehensive genomic profiling), and polygenic risk score testing.

Note: Please see the following related documents for additional information:

Position Statement

Medically Necessary:

Gene Panel Testing for Inherited Diseases

Testing for hereditary retinal disorders using gene panels is considered medically necessary for an individual with a suspected inherited retinal degenerative disease when results of the panel are likely to guide treatment decisions.

Testing for Ashkenazi Jewish associated inherited disorders using gene panels is considered medically necessary for an individual with suspected genetic disease or as part of preconception or prenatal genetic screening of a parent or prospective parent to determine carrier status when the parent or prospective parent is of Ashkenazi Jewish descent and when genetic counseling, which encompasses all of the following components, has been performed:

  1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
  2. Education about inheritance, genetic testing, disease management, prevention and resources; and
  3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
  4. Counseling for the psychological aspects of genetic testing.

Gene Panel Testing for Cancer Susceptibility and Management

Testing for Lynch syndrome (Hereditary Non-Polyposis Colorectal Cancer) using gene panels (containing 5-50 genes) is considered medically necessary when the panel contains, at a minimum, the following genes: EPCAM, MLH1, MSH2, MSH6, and PMS2, and an individual meets criteria for Lynch syndrome (Hereditary Non-Polyposis Colorectal Cancer [HNPCC]) genetic testing according to CG-GENE-15.

Testing for breast cancer susceptibility using gene panels (containing 5-50 genes) is considered medically necessary when the panel contains, at a minimum, the following genes: ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, and RAD51D, and an individual meets criteria for BRCA genetic testing according to CG-GENE-16.

Testing for prostate cancer using gene panels is medically necessary when the criteria below are met:

  1. The panel evaluates homologous recombination repair (HRR) gene alterations; and
  2. The individual is a candidate for treatment using a poly (ADP-ribose)polymerase (PARP) inhibitor.

Note: The test should be performed using tumor tissue (not cell-free circulating tumor DNA, also known as liquid biopsy).

Testing for advanced non-small cell lung cancer using gene panels (containing 5-50 genes) is considered medically necessary prior to initiating first-line therapy when the panel contains, at minimum, the following genes (mutations, rearrangements, fusions, or amplifications): ALK, BRAF, EGFR, ERBB2 (HER2), KRAS, MET, NTRK, RET, and ROS1.
Note: The test should be performed using tumor tissue (not cell-free circulating tumor DNA, also known as liquid biopsy). For criteria relating to use of circulating tumor DNA panel testing, see GENE.00049.

Testing for initial evaluation of myelodysplastic syndromes (MDS) using gene panels (containing 5-50 genes) is considered medically necessary when the panel contains, at a minimum, the following genes: ASXL1, DNMT3A, EZH2, NRAS, RUNX1, SF3B1, SRSF2, STAG2, TET2, TP53, U2AF1, ZRSR2.

Testing for initial evaluation of acute myeloid leukemia (AML) using gene panels (containing 5-50 genes) is considered medically necessary when the panel contains, at a minimum, the following genes: ASXL1, BCR-ABL, c-KIT, CEBPA (biallelic), FLT3-ITD, FLT3-TKD, IDH1, IDH2, NPM1, PML-RAR alpha, RUNX1, and TP53.

Testing for initial evaluation of acute lymphoblastic leukemia (ALL) using gene panels (containing 5-50 genes) is considered medically necessary when the panel contains, at a minimum, the following genes: ABL1, ABL2, CRLF2, CSF1R, FLT3, IL7R, JAK1, JAK2, JAK3, PDGFRB, and SH2B3.

Whole Exome Sequencing (WES)

Whole exome sequencing is considered medically necessary in the evaluation of an individual who meets all of the following criteria 1, 2, and 3:

  1. Meets one of the following criteria:
    1. Multiple anomalies not specific to a well-delineated genetic syndrome apparent before 1 year of age; or
    2. Apparently non-syndromic developmental delay/intellectual disability with onset prior to 18 years of age; or
    3. For the evaluation of a live fetus with abnormal fetal anatomic findings which are characteristic of a genetic abnormality; and
  2. When the results of testing would confirm or establish a clinical diagnosis that may lead to changes in management; and
  3. Genetic counseling, which encompasses all of the following components, has been performed:
    1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
    2. Education about inheritance, genetic testing, disease management, prevention and resources; and
    3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
    4. Counseling for the psychological aspects of genetic testing.

Note: WES may include comparator WES testing of the biologic parents or sibling of the affected individual.

Molecular Profiling for the Evaluation of Malignancies

Molecular profiling is considered medically necessary for unresectable or metastatic solid tumors when all of the criteria below are met:

  1. The test is used to assess tumor mutation burden and identify candidates for checkpoint inhibition immunotherapy; and
  2. Individual has progressed following prior treatment; and
  3. Individual has no satisfactory alternative treatment options.

Note: The test should be performed using tumor tissue (not cell-free circulating tumor DNA, also known as liquid biopsy).

Not Medically Necessary:

Testing using gene panels is considered not medically necessary for all other indications, including when the medically necessary criteria above have not been met.

Whole exome sequencing is considered not medically necessary for all other indications, including when the medically necessary criteria above have not been met.

Investigational and Not Medically Necessary:

Whole genome sequencing is considered investigational and not medically necessary for all indications.

Molecular profiling is considered investigational and not medically necessary for all other indications, including when the medically necessary criteria above have not been met.

Polygenic risk score testing is considered investigational and not medically necessary for all indications.

Rationale

Gene Panel Testing for Inherited Diseases
The 2012 American Academy of Ophthalmology (AAO) recommends genetic testing be ordered at the initial visit for individuals with a suspected inherited retinal degenerative disease. The causative mutation can be identified in up to 60-80% of affected individuals, which can guide treatment decisions. The scope of genetic testing recommended varies, multi-gene testing may be necessary when there are multiple causative genes, while single gene analysis might be more appropriate for certain conditions. For diseases such as Leber congenital amarurosis (LCA), which is caused by multiple different genes, it can be more efficient to order a single test which has been designed to specifically evaluate for all of the known causative genes (Stone, 2012).

Advances in genetic testing technologies have led to the development and use of large-scale DNA sequencing, including but not limited to expanded carrier panels. Generally, carrier screening guidelines have focused on the assessment of individual conditions and ancestry. However, the effectiveness of this approach can be impacted by limited or inaccurate knowledge of ancestry and an increasingly multiethnic society. Approaches to screening have also been influenced by the recognition that while some genetic conditions occur more frequently in certain populations, genetic disorders are not limited to specific ethnic groups (Edwards, 2015).

According to the American College of Medical Genetics (ACMG):

The completion of the full human genome sequence, followed by dramatic improvement in the speed and cost of DNA sequencing and microarray hybridization analysis, has enabled the ascertainment of an unprecedented quantity of disease-specific genetic variants in a time frame suited to prenatal/preconception screening and diagnosis. Now it is possible, using new technologies, to screen for mutations in many genes for approximately the same cost as previously required to detect mutations in a single gene or a relatively small number of population-specific mutations in several genes. Commercial laboratories have begun to offer such expanded carrier screening panels to physicians and the public, but there has been no professional guidance on which disease genes and mutations to include (Grody, 2013).

The American College of Medical Genetics recommend carrier screening in individuals of Ashkenazi Jewish descent (Gross, 2008).

Gene Panel Testing for Cancer Susceptibility and Management
Until recently, genetic testing for cancer susceptibility was generally carried out by direct sequencing (Sanger) which analyzes a specific gene for a particular mutation. However, next generation sequencing, (including but not limited to massively parallel sequencing and microarray testing) has made it possible to conduct panel testing which involves the analysis of multiple genes for multiple mutations simultaneously. Panel testing has the potential benefit of analyzing multiple genes more rapidly and thereby providing the results of the genetic work-up in a more timely fashion. However, the newer sequencing techniques may be associated with a higher error rate and lower diagnostic accuracy than direct sequencing which could affect the clinical validity of testing. Another potential drawback of the newer technologies is that they may provide information on genetic mutations which is of uncertain clinical significance. In assessing the value of a specific genetic testing panel for susceptibility to a particular malignant condition, consideration should be given to the peer-reviewed, published literature addressing the analytical validity, clinical validity, and clinical utility of the test. Evidence demonstrating a positive impact of the panel on the care of individuals with, or at risk for, a specific cancer should be considered. Use of gene panels is considered in accordance with generally accepted standards of medical practice to assess individuals at risk for Lynch syndrome (hereditary non-polyposis colorectal cancer) and breast cancer, and to evaluate certain individuals with prostate cancer (testing for homologous recombination repair [HRR] gene alterations), advanced non-small cell lung cancer, myelodysplastic syndrome, acute myeloid leukemia, and acute lymphoblastic leukemia.

The American Society of Clinical Oncology (ASCO) last issued a policy statement update regarding genetic and genomic testing for cancer susceptibility in 2015. The findings and conclusions regarding the state of the technology are summarized as follows:

Colorectal Cancer Susceptibility
Various laboratories offer next-generation sequencing panels (including but not limited to massively parallel sequencing, and microarray testing), making it possible to conduct panel testing which involves the analysis of multiple genes for multiple mutations simultaneously. The ColoNext™ test (manufactured by Ambry Genetics), which tests for variants in 17 genes, is one such example. Of the 17 genes tested, 12 are considered by the 2021 NCCN guideline on genetic/familial high-risk assessment for colorectal cancer to have well-established evidence of association with colorectal risk. The guideline notes that evidence is well-established for the following colorectal genes that are commonly included in gene panels: APC, BMPR1A, EPCAM, MLH1, MSH2, MSH6, MUTYH biallelic pathogenic variants, PMS2, PTEN, SMAD4, STK11 and TP53.

Lynch syndrome is an autosomal dominant disorder that is caused by a germline mutation in one of several DNA mismatch repair genes or loss of expression of MSH2 due to deletion in the EPCAM gene (previously called TACSTD1). The mismatch repair (MMR) genes that are associated with Lynch syndrome include:

The 2021 NCCN guideline on genetic/familial high-risk assessment for colorectal cancer recommends that testing for Lynch syndrome (EPCAM, MLH1, MSH2, MSH6, and PMS2 sequence analysis) includes individuals who meet the Bethesda guidelines, the Amsterdam II criteria, who have a cancer diagnosis prior to age 50, or have a predicted risk for Lynch syndrome greater than 5% on one of the following prediction models: MMRpredict, MMRpro or PREMM5. Use of targeted gene panels (containing 5-50 genes) that include EPCAM, MLH1, MSH2, MSH6, and PMS2 is considered in accordance with generally accepted standards of medical practice.

Breast Cancer Susceptibility
Multi-gene testing for hereditary forms of cancer can analyze a set of genes which are associated with a specific family cancer type. Multi-gene panel testing can impact medical management and can provide an association for prediction of risk of breast cancer. However, not all genes tested show a strong association for breast cancer. It’s important to define which genes are most useful clinically as not all genes available on multi-gene tests are clinically actionable.

In the 2022 National Comprehensive Cancer Network® NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for genetic/familial high-risk assessment: breast, ovarian, and pancreatic, recommendations are made for genetic panel testing using these genes ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, and CDH1.

Study among cancer susceptibility genes and breast cancer risk continues. Two case-control studies have been published which analyzed various genes which are susceptible for breast cancer risk. A 2021 study by Dorling and colleagues looked at a panel of 34 susceptible genes from samples of 60,466 individuals with breast cancer and 53,461 controls from 25 countries. The objective was the estimated odds ratios for breast cancer overall and tumor subtypes. Using the Cancer Risk Estimates Related to Susceptibility (CARRIERS) population-based studies of breast cancer in the United States, Hu and colleagues (2021) reported on 17 studies and analyzed 28 genes (predisposed to cancer) in 32,247 participants (case group) with breast cancer compared to 32,544 unaffected participants (control group). The objective was the association between variants in each gene and risk of breast cancer. Significant associations between breast cancer and variants in 8 genes: ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, and RAD51D were found in both studies. Of note, several genes regarded as having strong evidence of an association with breast cancer risk, for example, CDH1, PTEN, STK11, and TP53, are very rare and did not show a significant association, presumably given their low prevalence. The majority of mutations among case subjects were BRCA1, BRCA2, and PALB2, and among controls, CHEK2 and ATM, reflecting the higher and lower penetrance of the genes respectively. BRCA1, BRCA2, and PALB2 are associated with a high risk of breast cancer (with odds ratios ranging from 5.0 to 10.6 in the study by Dorling et al.), and mutations in CHEK2 and ATM are associated with a moderate risk (with odds ratios ranging from 2.1 to 2.5). Use of targeted gene panels (containing 5-50 genes) is considered in accordance with generally accepted standards of medical practice.

Management of Prostate Cancer
In 2020, the FDA updated the label for Lynparza (Olaparib), a poly(ADP-ribose) polymerase (PARP) inhibitor, to include individuals with deleterious or suspected deleterious germline or somatic HRR gene-mutated metastatic-resistant prostate cancer who have progressed following previous treatment and for therapy based on an FDA-approved companion diagnostic test for Lynparza. The label was updated again in 2021 with no change to the above recommendation. This approval was based on the PROfound trial (NCT02987543). In 2020, de Bono and colleagues reported on a randomized, open-label, phase 3 trial which evaluated the use of olaparib in individuals with metastatic castration-resistant prostate cancer with disease progression while receiving a hormonal agent. All participants had a tumor mutation in one of the genes involved in the homologous recombinant repair (HRR) pathway. Participants were divided into two cohorts; cohort A included 245 participants who had at least one alteration in BRCA1, BRCA2, or ATM. Cohort B included 142 participants who had alterations in any of the other 12 prespecified genes (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A,RAD51B, RAD51C, RAD51D and RAD54L). Primary endpoint was progression-free survival in cohort A. Participants were randomized in a 2:1 fashion to receive either olaparib or hormonal agent (control). The authors report that in cohort A, progression-free survival was a median of 7.4 months for those taking olaparib compared to a median of 3.6 months in the control group. Median overall survival in cohort A was 18.5 months for those taking olaparib compared to a median overall survival of 15.1 months in the control group. The final analysis of overall survival was reported by Hussain and colleagues (2020). In cohort A, median duration of overall survival was 19.1 months with olaparib and was 14.7 months in the control group. In cohort B, median duration of overall survival was 14.1 months with olaparib and 11.5 months in the control group. The overall population (cohorts A and B) had a median duration of overall survival of 17.3 months for those taking olaparib and 14.0 months for those in the control group. The study authors note that the role of PPP2R2A could not be validated as a homologous recombination repair gene based on preclinical data and there was no benefit of overall survival with treatment of olaparib over control therapy in the individuals who had alterations in PPP2R2A. The FDA label also notes that while individuals with gene mutations for PPP2R2A were enrolled in the trial, Lynparza is not indicated for those with this gene mutation due to unfavorable risk-benefit.

In addition to Olaparib, several other PARP inhibitors have been evaluated in treating men with metastatic prostate cancer and a pathogenic variant in an HRR gene (or genes involving DNA damage response pathways), including Rucaparib, Niraparib, and Talazoparib.

Management of Non-Small Cell Lung Cancer
Gene alterations have been identified which can impact selection of therapy. Testing of specimens for gene alterations can help identify potentially effective targeted therapy and avoid therapy unlikely to provide clinical benefit. In the 2021 NCCN Clinical Practice Guidelines in Oncology for non-small cell lung cancer, they recommend molecular testing for actionable biomarkers (with these specified genes ALK, BRAF, EGFR, ERBB2 (HER2), KRAS, MET, NTRK, RET and ROS1) prior to administering first-line therapy. Use of targeted gene panels (containing 5-50 genes) is considered in accordance with generally accepted standards of medical practice.

Myelodysplastic syndromes
Myelodysplastic syndromes are conditions that can occur when the cells in bone marrow are abnormal and have problems making new blood cells. It is considered to be a type of cancer. Researchers have found that mutations in certain genes are disease-related and can be presumptive of myelodysplastic syndromes. The 2022 NCCN guideline for myelodysplastic syndromes notes the following genes are frequently somatically mutated in myelodysplastic syndromes: ASXL1, DNMT3A, EZH2, NRAS, RUNX1, SF3B1, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2.Use of targeted gene panels (containing 5-50 genes) is considered in accordance with generally accepted standards of medical practice.

Acute Myeloid Leukemia
Acute myeloid leukemia is a type of cancer that starts in the bone marrow. It can move into the bloodstream and spread to other parts of the body including the lymph nodes, liver, spleen, central nervous system, and testicles. There are several gene variants which are associated with specific prognosis for AML. The 2022 NCCN guidelines for acute myeloid leukemia recommend testing for ASXL1, BCR-ABL, c-KIT, CEBPA (biallelic), FLT3-ITD, FLT3-TKD, IDH1, IDH2, NPM1, PML-RAR alpha, RUNX1, and TP53. Use of targeted gene panels (containing 5-50 genes) is considered in accordance with generally accepted standards of medical practice.

Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia is a type of cancer that starts in the bone marrow. It can progress quickly and develops from immature forms of white blood cells. It can move into the bloodstream and spread to other parts of the body including the lymph nodes, liver, spleen, central nervous system, and testicles. The 2021 NCCN guidelines for acute lymphoblastic leukemia recommend testing for ABL1, ABL2, CRLF2, CSF1R, FLT3, IL7R, JAK1, JAK2, JAK3, PDGFRB, and SH2B3. Information regarding these gene variants may aid in risk stratification. Use of targeted gene panels (containing 5-50 genes) is considered in accordance with generally accepted standards of medical practice.

Unselected Population Screening
As part of a population health study targeting Nevada’s diverse demographics (the Healthy Nevada Project), Grzymski and colleagues (2020) reported on the genetic risk and disease manifestation of three inherited autosomal dominant conditions: BRCA-related hereditary breast and ovarian cancer, Lynch syndrome, and familial hypercholesterolemia. With a cohort of 26,906 participants, the authors identified 214 unique pathogenic or likely pathogenic variants carried by 358 individuals (1.33%). Of the 273 carriers with medical records available for review, 60 participants were identified as having clinical disease relevant to the underlying carrier status (21.9%). There were 135 individuals with hereditary breast and ovarian cancer with records available which revealed 28 individuals with disease who were also carriers (20.7%) compared with 523 individuals with disease who were not carriers (2.6%). Records were available for 66 individuals who were carriers of Lynch syndrome. A diagnosis of colon or other cancer was found in 19 participants (28.8%). The prevalence in non-carriers was 0.5% (92 individuals with disease). The records of 73 individuals with familial hypercholesterolemia were reviewed. The prevalence of hyperlipidemia in carriers was 53.4% compared to 25.7% in non-carriers. Net health outcomes were not assessed. While these results suggest genetic screening for certain conditions has potential in identifying at-risk carriers not detected in medical practice, a population health screening approach could underestimate the impact of preventive screening in larger populations with diverse cohorts. There is potential for overinterpretation of disease risk along with ethical and social factors. The risk of benefits of population-based screening programs need to be carefully assessed with long-term studies; at this time, application is not considered in accordance with generally accepted standards of medical practice.

Whole Exome Sequencing (WES)
It is estimated that most disease-causing mutations (around 85%) of clinically important sequence variants occur within the regions of the genome that encode proteins. While similar to whole genome sequencing (WGS), WES reads only the parts of the human genome that encode proteins, leaving the other regions of the genome unread (Choi, 2009). Since most of the errors that occur in DNA sequences that then lead to genetic disorders are located in the exons, sequencing of the exome is being explored as a more efficient method of analyzing an individual's DNA to discover the genetic cause of diseases or disabilities. It has been theorized that sequencing of the human exome can be used to identify genetic variants in individuals to diagnose diseases.

A potential major indication of WES is the establishment of a molecular diagnosis in individuals with a phenotype that is suspicious for a genetic disorder or for individuals with known genetic disorders that have a large degree of genetic heterogeneity involving substantial gene complexity. Such individuals may be left without a clinical diagnosis of their disorder, despite a lengthy diagnostic work-up involving a variety of traditional molecular and other types of conventional diagnostic tests. For some of these individuals, WES, after initial conventional testing has failed to make the diagnosis, may return a likely pathogenic variant. Results of WES testing are intended to guide treatment decisions including confirming or establishing a clinical diagnosis that may lead to changes in management (which may in some cases, may obviate the need for further testing, and/or end the diagnostic odyssey).

The 2021 Practice Guideline by the ACMG provides exome sequencing and genome sequencing recommendations for children with congenital anomalies or intellectual disability (Manickam, 2021) based on an assessment of 167 studies, 36 of which had a participant population greater than 20 individuals. The guidelines strongly recommend whole exome/genome sequencing as a first-tier or second-tier test (guided by clinical judgment and often clinician–member/family shared decision making after CMA or focused testing) for individuals with one or more congenital anomalies prior to one year of age or for individuals with developmental delay (DD) or intellectual disability with onset prior to 18 years of age:

The literature supports the clinical utility and desirable effects of whole exome/genome sequencing on active and long-term clinical management of patients with congenital anomalies, or developmental delay or intellectual disability, and on family-focused and reproductive outcomes with relatively few harms. Compared with standard genetic testing, whole exome/genome sequencing has a higher diagnostic yield.

The guidelines also note that WES, which only evaluates the coding regions of the genome, is widely available, with extensive experience interpreting and comparing test results. At this time, WGS, which provides additional assessment of non-coding regions of the genome is limited to small number of clinics and labs. The ACMG includes WES in their guideline statement merely with the expectation that WES will become more commonly used and available.

For fetal testing, recommendations are made in a 2018 joint position statement from the International Society for Prenatal Diagnosis, the Society for Maternal Fetal Medicine, and the Perinatal Quality Foundation on the use of genome-wide sequencing. For fetal diagnosis, the authors recommend:

The use of diagnostic sequencing is currently being introduced for evaluation of fetuses for whom standard diagnostic genetic testing, such as chromosomal microarray analysis (CMA), has already been performed and is uninformative or is offered concurrently according to accepted practice guidelines, or for whom expert genetic opinion determines that standard genetic testing is less optimal than sequencing for the presenting fetal phenotype.

Historically, prenatal diagnosis has been performed using G-banded karyotyping to detect chromosomal abnormalities. The yield in this approach results in a diagnosis in 9-19% of fetal anomalies. The use of CMA provides an additional 6% yield. Cause of the majority of fetal anomalies is unknown. Identifying the cause of fetal anomalies can help determine prognosis, inform recurrence risk, and guide clinical management. Prior studies of use of exome sequencing to diagnose unexplained fetal anomalies showed diagnostic yields of 8.5% and 10% (Petrovski, 2019; Lord, 2019). The relatively low yields might be explained by the wide range of structural anomalies which were included. There is limited data regarding the usefulness of exome sequencing for diagnosis of specific, severe prenatal phenotypes. In a 2020 study by Sparks and colleagues the authors reported on the diagnostic yield of exome sequencing in detecting pathogenic or pathogenic variants in 127 participants with unexplained cases of nonimmune hydrops fetalis (NIHF). The presence of NIHF was defined by fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or combination of the conditions. There were 37/127 cases in which the authors identified diagnostic genetic variants. Overall there were 25/37 cases in which diagnostic variants were autosomal dominant (12% of those were inherited and 88% were de novo). Autosomal recessive diagnostic variants were found in 10/37 cases (95% inherited and 5% de novo). Potentially diagnostic variants were identified in 12 additional cases.

WES presents ethical questions about informing individuals about incidental findings that have clinical significance. Ongoing discussions continue to explore whether or not, and how to inform individuals about medically relevant mutations in genes unrelated to the diagnostic question (that is, mutations of unknown significance, non-paternity and sex chromosome abnormalities). This type of information may not only affect the individual being tested, but may also implicate family members.

The 2021 Practice Guideline by the ACMG (Manickam, 2021) notes:

ES is available widely as a clinical tool with a number of commercial and academic laboratories offering this testing. Best practice includes familial comparators (“trio”) if available to help contextualize rare variants, but also can be effectively performed as proband only or duo, with diagnostic yield being slightly reduced compared with trio testing.

While some of the potential advantages of WES include the fact that it can be carried out more quickly than traditional genetic testing, it is not without limitations. WES typically covers only 85-95% of the exome and has no, or limited coverage of other areas of the genome. Areas of concern with this technology include: (1) gaps in the identification of exons prior to sequencing; (2) the need to narrow the large initial number of variants to manageable numbers without losing the likely candidate mutation; (3) difficulty identifying the potential causative variant when large numbers of variants of unknown significance are generated for each individual. It is more difficult to detect chromosomal changes, duplications, large deletions, rearrangements, epigenetic changes or nucleotide repeats from WES data compared with other genomic technologies (ACMG, 2012; Teer, 2010[a]; Teer, 2010[b]). Other uses of WES are not considered in accordance with generally accepted standards of medical practice.

Whole Genome Sequencing
WGS, also known as full genome sequencing (FGS), complete genome sequencing, or entire genome sequencing, is a laboratory procedure which seeks to determine an individual's entire DNA sequence, specifying the order of every base pair within the genome at a single time. WGS allows researchers to study the 98% of the genome that does not generally contain protein-coding genes. In the clinical setting, this process frequently involves obtaining a DNA sample from the individual (typically from blood, saliva, or bone marrow) and sequencing an individual's entire chromosomal and mitochondrial DNA. Because of the large volume of genomic data involved in this process, the genomic information is processed by and stored on microprocessors and computers.

A 2021 randomized trial by Krantz and colleagues reported on the effect of WGS in the clinical management of 354 acutely ill infants. Participants included acutely ill infants in pediatric intensive care units, aged between 0 and 120 days with a clinical suspicion of a genetic disorder. Participants were randomized to receive WGS test results either 15 days (the early group, n=176) or 60 days (the delayed group, n=178) after testing with a total 90-day observation window. Primary outcome was the difference in the number of participants who had a change in management in the early and delayed groups at 60 days. Change in management was defined as having no change in care, a condition-specific intervention, condition-specific supportive care, palliative care, or a combination of the latter. Secondary outcome measures included diagnostic efficacy of WGS, change of management at 90 days, length of hospital stay, and mortality. At 60 days, in the early group, diagnostic efficacy was found in 55/176 infants and a change in management was noted in 34/161 infants. At 60 days in the delayed group, diagnostic efficacy was found in 27/178 infants with a change in management in 17/165 infants. At 90 days, in the early group, diagnostic efficacy was noted in 55/176 infants with a change in management in 38/159 infants. At 90 days, in the delayed group, diagnostic efficacy was noted in 56/178 infants with a change in management noted in 45/161 infants. The most frequent changes in management at 60 days were condition-supportive care and included subspecialty referrals and medication changes. There were no significant differences regarding mortality and length of hospital stay between the early and delayed groups. Given the 90-day observation window, it is likely other changes in management may not have been captured. There is also a lack of validated instruments in testing individual- and family-reported outcomes.

Researchers continue to explore the relationship between mutations in the genomic material and the development or presence of disease. The clinical role of WGS has yet to be established. Research is still being done to determine if WGS can be used to accurately identify the presence of a disease, predict the development of a particular disease in asymptomatic individuals as well as how an individual might respond to pharmacological therapy. It has been theorized that WGS might eventually improve clinical outcomes by preventing the development of disease.

Cytogenomic Microarray Analysis
Cytogenomic microarray analysis collectively describes two different laboratory techniques: array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays. While both of these techniques detect copy number variants (CNVs), they identify different types of genetic variation. aCGH allows the detection of gains and losses in DNA copy number across the entire genome without prior knowledge of specific chromosomal abnormalities. SNP arrays allow genotyping based on allele frequency. SNP arrays have additional oligonucleotide probes which analyze thousands of SNPs throughout the genome in order to identify deletions and duplications. The use of cytogenomic microarray analysis as a diagnostic tool for congenital anomalies as well as for individuals with unexplained developmental delay (DD), autism spectrum disorder (ASD) or intellectual disability (intellectual developmental delay) is specifically addressed by CG-GENE-10 Chromosomal Microarray Analysis (CMA) for Developmental Delay, Autism Spectrum Disorder, Intellectual Disability and Congenital Anomalies.

Molecular Profiling
Molecular profiling, also called comprehensive genomic profiling, is a method for identifying multiple biomarkers in the malignant tumors of persons who have cancer. The biomarker information can be used to identify treatment options. The personalized tumor molecular profiling services or test panels addressed in this document are similar in that they all evaluate tumor tissue and, from it, produce a molecular profile of the tumor and a list of potential therapies. However, their individual testing methods vary from matching over expressed genes with drugs to more complex systems biology approaches. Large multi-biomarker panels test a variety of markers. It is often the case that not every test in these panels has a proven benefit.

Some commercially available molecular profile panels are listed below:
FoundationOne
FoundationOne uses next generation sequencing (NGS) “to interrogate the entire coding sequence of 236 cancer-related genes (3769 exons) plus 47 introns from 19 genes frequently altered or rearranged in cancer.” FoundationOne helps match the genomic alterations present in a tumor with specific targeted therapies or clinical trials. Recent small studies (Drilon, 2013; Lipson, 2012; Vignot, 2013) have investigated next generation sequencing in individuals with lung cancer. Others have used next generation sequencing in those with breast cancer (Ross, 2013a); colorectal and other gastrointestinal cancers (Dhir, 2017; Gong, 2017; Lipson, 2012), ovarian cancer (Ross, 2013b), and prostate cancer (Beltran, 2013). Limitations of these studies include small sample sizes and lack of randomization.

FoundationOne CDx
On November 30, 2017, the FDA approved the FoundationOne CDx NGS sequencing test as a companion diagnostic for several drugs including: Gilotrif® (afatinib), Iressa® (gefitinib), Tarceva® (erlotinib), Tagrisso® (osimertinib), Alecensa® (alectinib), Xalkori® (crizotinib), Zykadia® (ceritinib), Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib), Tafinlar® (dabrafenib), Zelboraf® (vemurafenib), Mekinist® (trametinib), Cotellic® (cobimetinib) in combination with Zelboraf® (vemurafenib), Herceptin® (trastuzumab), Kadcyla® (ado-trastuzumabemtansine), Perjeta® (pertuzumab), Erbitux® (cetuximab), Vectibix® (panitumumab), and Rubraca® (rucaparib). In addition, the test detects substitutions and alterations in 324 genes and is indicated to provide general tumor mutation profiling of solid malignant neoplasms in accordance with professional guidelines in oncology.

The FDA approval was based on concordance studies that compared the Foundation One CDx test to approved specific companion diagnostic tests including the cobas® EGFR Mutation Test (EGFR exon 19 deletions, L858R, EGFR T790M), Ventana ALK CDx Assay (ALK), Vysis ALK Break-Apart FISH Probe Kit (ALK), therascreen® KRAS RGQ PCR Kit (KRAS), Dako HER2 FISH pharmDx® Kit (ERBB2 [HER2]), cobas® BRAF V600 Mutation Test (BRAF V600), THxID BRAF kit (BRAF V600), and FoundationFocus CDxBRCA (BRCA1 and BRCA2). The sample size for each biomarker comparison study ranged from 175 to 342, the positive percent agreement ranged from 89.4% to 100%, and the negative percent agreement ranged from 86.1% to 100%. For the BRCA1 and BRCA2 mutation, the FoundationOne CDx was considered concordant based on the previous approval of the FoundationFocus CDxBRCA test. The FDA states, “The clinical concordance studies, with the exception of ALK and EGFR T790M, were subject to pre-screening bias, therefore the concordance results may be overestimated and the failure rate may be underestimated.” For the T790M mutation, there is ongoing research to determine why a subset population with a mutant allele frequency < 5% tested negative with the cobas EGFR Mutation Test v2 but tested positive with the FoundationOne CDx test. The FDA concluded that, overall, the FoundationOne CDx test demonstrated non-inferiority to the corresponding specific companion diagnostic tests (FDA, 2017a). On March 16, 2018, the Centers for Medicare and Medicaid Services (CMS) approved NGS-based in vitro companion diagnostic laboratory tests for national coverage after an FDA-CMS parallel review.

In 2018, Hellmann and colleagues reported results from the CheckMate 227 study, an open-label, phase 3 trial (NCT02477826) designed to evaluate the efficacy of nivolumab or nivolumab-based regimens as first-line therapy in participants with stage IV or recurrent non-small cell lung cancer (NSCLC) that have not previously received chemotherapy as primary therapy. Trial participants were stratified into PD-L1 expression levels (at least 1% or less than 1%). In addition, tumor mutation burden was determined using the FoundationOne CDx assay. At 1 year, the progression-free survival (PFS) rate for participants with a high tumor mutation burden that received nivolumab in combination with ipilimumab was 42.6% versus 13.2% for the chemotherapy group. The median PFS was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) for participants that received nivolumab in combination with ipilimumab versus 5.5 months for the chemotherapy group (95% CI, 4.4 to 5.8) (HR for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The authors concluded:

Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy alone among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection.

Additional data regarding the CheckMate 227 study was published by Hellmann and colleagues in 2019. The authors reported on the overall survival with nivolumab plus ipilimumab compared to chemotherapy in participants with a tumor PD-L1 expression level of 1% or greater. There were 679 participants who had evaluation of tumor mutation burden which showed a similar degree of overall survival regardless of whether they had a high tumor mutation burden or a low tumor mutation burden. The authors conclude:

…although absolute survival with nivolumab plus ipilimumab was greatest in patients with a high tumor mutational burden, a similar relative benefit of nivolumab plus ipilimumab, as compared with chemotherapy, was seen in patients regardless of tumor mutational burden.

Based on this data showing no difference in survival outcomes between individuals whose tumors had high or low levels of tumor mutation burden, Bristol-Myers Squibb announced its decision in January 2019 to withdraw the supplemental biologics license application with the FDA seeking approval for the combination of nivolumab and ipilimumab for individuals with advanced NSCLC with tumor mutational burden greater than or equal to 10 mutations per megabase.

The 2022 NCCN guideline for NSCLC notes that the emerging biomarker tumor mutation burden may be helpful to identify eligibility of first-line therapy with nivolumab with or without ipilimumab for those with NSCLC, however there is no consensus regarding how to measure tumor mutation burden.

In June 2020, the FDA updated the label for pembrolizumab (Keytruda® [Merck, Kenilworth, NJ]) to include treatment for individuals with unresectable or metastatic solid tumors with tumor mutation burden-high (defined as greater than or equal to 10 mutations per megabase) when confirmed by an FDA-approved test following progression after prior treatment and no satisfactory alternative treatment options. According to the FDA label, the accelerated approval was based on the Keynote-158 trial (NCT02628067), a multicenter, non-randomized, open-label trial. Efficacy outcomes were tumor response rate and duration of response. Tumor mutation burden was assessed by the Foundation One CDx assay. Of the 1050 subjects enrolled in the efficacy analysis population, tumor mutation burden was analyzed in 790 subjects. There were 102 subjects who had tumors identified as tumor mutation burden-high. With a median follow-up time of 11.1 months, 29% of participants reached an objective response rate, 4% reached a complete response, and 25% reached a partial response. Duration of response was assessed at 57% with a duration of greater than or equal to 12 months and 50% with a duration of greater than or equal to 24 months. Continuation of approval may be contingent on verification and description of clinical benefit in confirmatory trials.

Other Tests
Other tests are becoming available on the market. One such example is the Oncotype MAPPanCancer Tissue Test (Paradigm Diagnostics, Inc., Phoenix, AZ) in which next-generation sequencing is used to identify genetic alterations among 257 genes to match appropriate targeted therapy for tumor mutation burden of solid tumors.

Whole transcriptome testing can assist in determining how cells normally function and how changes in gene activity can contribute to disease by showing what genes are active in which cells. DNA is the molecule which contains instructions needed to build and maintain cells. In order for the instructions to be read and completed, the DNA has to be read and transcribed (that is, copied into RNA). The testing involves the presence and amount of RNA. By analyzing the RNA, it is possible to count the transcripts to determine the amount of gene activity.

Molecular Intelligence Service or Target Now
A widely used tumor molecular profile has been the Target Now Molecular Profiling Service. According to the Caris Life Sciences website, their tumor profiling service is now being promoted as the Molecular IntelligenceService. The published literature addressing these services is limited. Von Hoff and colleagues (2010) evaluated 86 individuals with refractory metastatic cancer. PFS using a treatment regimen selected by Target Now molecular profiling of a malignant tumor was compared with the PFS of the most recent treatment regimen on which the individual experienced progression. A molecular target was detected in 84 of 86 (98%) participants. A total of 66 (78.6%) individuals were treated according to the molecular profile results with 18 of the 66 (27%) having a PFS ratio (defined as PFS on molecular profile–selected therapy or PFS on prior therapy) of greater than or equal to 1.3 (95% CI, 17% to 38%; p=0.007).

An editorial (Doroshow, 2010) accompanying the study reported that the trial had a number of significant limitations, including uncertainty surrounding the achievement of time to progression (the study’s primary endpoint), and a lack of a randomized design. Additional limitations include a small number of participants and lack of duplication of study results by an independent dataset.

Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)
Cheng and colleagues (2015) developed and evaluated the MSK-IMPACT, “a hybridization capture-based assay targeting all coding regions of 341 oncogenes and tumor suppressors.” The ability of the assay to detect single nucleotide variants (SNVs) and short insertions and deletions (indels) was assessed in 284 known positive solid tumor samples. Of these, 75 had a matched normal sample available. The authors reported successful detection of known variants in all 284 cases, and ability to achieve high degrees of resolution and levels of coverage to > 500x in tumor samples that allows low-frequency mutations to be detected. On November 15, 2017, the FDA granted marketing authorization for MSK-IMPACT based on a de novo request (FDA 2017b).

Other Molecular Profiling
Other molecular profiling such as, GeneKey, GeneTrails Solid Tumor Panel, MatePair, MyAML, OmniSeq, OnkoMatch, OncInsights, and SmartGenomics have less published validation. To date, there is insufficient peer-reviewed evidence specifically validating these tests.

In 2012, Tsimberidou and colleagues developed a personalized medicine program at a single facility in the context of early clinical trials. Their goal was to observe whether molecular analysis of advanced cancer and use of targeted therapy to counteract the effects of specific aberrations would be associated with improved clinical outcomes. Participants with advanced or metastatic cancer refractory to standard therapy underwent molecular profiling. A total of 175 subjects were treated with matched therapy, and the overall response rate was 27%. Of the 116 subjects treated with non-matched therapy, the response rate was 5%. The median time-to-failure was 5.2 months for those on matched therapy versus 2.2 months on non-matched therapy. At a median of 15 months follow-up, median survival was 13.4 months versus 9.0 months in favor of matched therapy.

Jameson and colleagues (2013) performed a small pilot study investigating multi-omic molecular profiling (MMP) for the selection of breast cancer treatment. MMP treatment recommendations were selected in 25 cases and original treatment plans were revised accordingly. Partial responses were reported in 5/25 (20%), stable disease in 8/25 (32%) and 9/25 had no disease progression at 4 months. This study was limited by its small size and non-randomization. A large randomized prospective trial is needed for further evaluation.

Primarily marketed to researchers, Life Technologies Inc. offers several variations of their Ion Torrent Next Generation Sequencing Ion AmpliSeq panels, according to the company website. The Ion AmpliSeq Comprehensive Cancer Panel analyzes more than 400 cancer-related genes and tumor suppressor genes. The Ion AmpliSeq Cancer Hotspot Panel v2 analyzes the “hotspot” regions of 50 cancer-related and tumor suppressor genes.

Studies on Molecular Profiling Therapy
LeTourneau and colleagues (2012, 2015) reported on an open-label, randomized controlled phase II trial of treatment of refractory metastatic solid tumors directed by molecular profiling versus standard of care treatment (SHIVA trial). A total of 195 adults, consisting of 99 in the experimental group and 96 in the control group, were enrolled from eight academic centers in France. The primary outcome was progression-free survival (PFS) analyzed by intention-to-treat. Randomization was stratified by three molecular pathways (hormone receptor pathway, PI3K/AKT/mTOR pathway, and RAF/MEK pathway). Molecular analysis included targeted NGS, gene copy number alterations and hormone expression by immunohistochemistry. The molecularly targeted drugs used in the experimental group were approved for clinical use in France, but were outside their indications. The control group received standard treatment chosen by the physician. Median follow-up was 11.3 months for both the experimental and control groups at the time of primary analysis of PFS. Median PFS was 2.3 months (95% CI, 1.7-3.8) in the experimental group versus 2.0 months (95% CI, 1.7-2.7 months) in the control group (hazard ratio, 0.88; 95% CI, 0.65-1.19; p=0.41). Upon subgroup analysis, there was no statistically significant difference in PFS between the two groups. Objective responses were reported for 4 of 98 (4.1%) assessable subjects in the targeted treatment group versus 3 of 89 (3.4%) assessable subjects in the standard care group. Among the safety population, grade 3-4 adverse events were reported for 43 of the 100 subjects (43%) who received a molecularly targeted agent and 32 (35%) of 91 subjects treated in the control group. The authors suggested that “off-label use of molecularly targeted agents should be discouraged and enrollment in clinical trials should be encouraged to help identify predictive biomarkers of efficacy.”

Presley and colleagues (2018) conducted a multicenter, retrospective, cohort study to compare broad-based genomic sequencing to routine EGFR and ALK biomarker testing in individuals with advanced NSCLC (stage IIIB/IV or unresectable nonsquamous). The primary outcomes were the 12-month mortality and overall survival from the start of first-line treatment. The researchers examined the Flatiron Health Database records of 5688 individuals (median age 67 years) who received care for advanced NSCLC between January 1, 2011 and July 31, 2016: 875 received broad-based genomic sequencing (multigene panel testing assay of more than 30 genes) and 4813 received routine EGFR/ALK testing. Subjects were required to have documented broad-based genomic sequencing testing or EGFR testing; if EGFR was negative, ALK testing was required. All subjects received at least one line of systemic antineoplastic treatment. At 12 months, the unadjusted mortality rates were 49.2% for the broad-based group and 35.9% for the EGFR/ALK group. Of the subjects in the broad-based group, 4.5% received targeted treatment based on test results, 9.8% received EGFR/ALK targeted treatment, and 85.1% received no targeted treatment. When using an instrumental variable analysis, no significant association was found between broad-based genomic sequencing and 12-month mortality (difference in the predicted probability of death at 12 months between the groups: −3.6%; 95% CI, −18.4% to 11.1%; p=0.63). The predicted probability of 12-month mortality was 44.4% (95% CI, 42.9% to 45.9%) in the EGFR/ALK group and 41.1% (95% CI, 27.7% to 54.5%) in the broad-based group. For the propensity score-matched sample, the overall survival was not significantly different between the groups (42.0% vs. 45.1%; 0.92 HR; 95% CI, 0.73 to 1.11; p=0.40). The researchers concluded that “among patients receiving care for advanced NSCLC in the community oncology setting, broad-based genomic sequencing directly informed treatment in a minority of patients and was not independently associated with better survival.” Limitations of the study included a relatively small and homogenous sample for the broad-based group and the possible inaccuracy of the electronic health records.

Other Considerations
The 2022 NCCN Guidelines do not contain recommendations for the general strategy of testing a tumor for a wide range of biomarkers. However, the guidelines do contain recommendations for specific genetic testing for individual cancers, when there is a known drug-biomarker combination that has demonstrated benefits for that particular type of tumor, such as colon or NSCLC. In order to conserve tissue, the current NSCLC guidelines support an FDA approved NGS companion diagnostic test that can simultaneously test for EGFR mutations, BRAF mutations, ROS1 rearrangements, and ALK rearrangements.

A 2018 joint guideline (Lindeman, 2018), Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment with Targeted Tyrosine Kinase Inhibitors, from the CAP, International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) states that “multiplexed genetic sequencing panels are preferred over multiple single-gene tests to identify other treatment options beyond EGFR, ALK, and ROS1” (level of evidence rating: expert consensus opinion - serious limitations in quality of evidence). However, the authors note that “the strength of evidence is inadequate supporting the use of multiplexed genetic sequencing panels compared with single-gene tests.”

Polygenic Risk Score
Polygenic risk score testing measures multiple single nucleotide polymorphisms which have been proposed as being associated with a specific disease or condition. Using an algorithm, a number or score is created that is intended to provide an estimated prediction of the risk of some future health outcome. Polygenic risk scores have been proposed to estimate an individual's lifetime genetic risk of disease. Polygenic risk score tests are being developed for a number of conditions such as heart disease, diabetes, cancer, obesity, and schizophrenia.

In a 2020 study by Damask and colleagues, the authors sought to determine whether individuals with a high polygenic risk score for coronary artery disease had a higher incidence of major adverse cardiovascular events (MACE) and whether those individuals had greater risk reduction of events following treatment with alirocumab (given for hyperlipidemia). In this post-hoc analysis of participants from the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), there were 11,953 individuals who had available DNA samples. In this study the authors defined high genetic risk as those with greater than 90th percentile polygenic risk score. Those with less than or equal to 90th percentile were considered lower genetic risk. MACE risk analysis was performed in the placebo arm while treatment benefit analysis was performed in all participants. In the placebo group, the incidence of MACE related to polygenic risk score for coronary artery disease was 17.0% for those with high genetic risk and 11.4% for those considered to be low genetic risk. In the group who received treatment (alirocumab), the absolute reduction in those with high polygenic risk score was 6.0% and 1.5% in the low polygenic risk score group. The relative risk reduction by alirocumab was 37% in the high polygenic risk score group and 13% in the low polygenic risk score group. With this ad-hoc analysis, further validation is necessary. The authors also used a top threshold (defined in this study as greater than 90th percentile). Lack of consistent threshold for polygenic risk scores across studies make it difficult to generalize these results. Furthermore, given that participants enrolled into the ODYSSEY OUTCOMES trial were already candidates for intensive lipid lowering therapy, the added clinical utility of polygenic risk scoring is uncertain.

Marston and colleagues (2020) also reported on an ad-hoc analysis of 14,298 participants (7163 in the evolocumab arm and 7135 in the placebo arm) from the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). The FOURIER trial was a multinational, randomized, double-blind, placebo-controlled trial which looked at the efficacy of evolocumab in individuals with atherosclerotic cardiovascular disease. In the Marston study, the authors sought to determine whether genetic risk score could risk-stratify individuals with atherosclerotic cardiovascular disease and predict benefit from evolocumab treatment. The authors looked at two outcomes; major coronary events (defined as coronary heart death, myocardial infarction, and coronary revascularization) and major vascular events (defined as major coronary events plus stroke). Those in the genetic cohort were followed for a median of 2.3 years. Genetic risk categories were measured as low, intermediate, or high. There were 1235 participants who had a major vascular event with 1074 of those being major coronary events. In the placebo arm, there were 774 participants who had a major vascular event, with 673 of those being major coronary events. Major vascular event rates in the low-genetic-risk category were 10.1%, 11.3% in the intermediate-genetic-risk category, and 13.8% in the high-genetic-risk category. Major coronary event rates in the low-genetic-risk category were 8.0%, 9.7% in the intermediate-genetic-risk category, and 13.2% in the high-genetic-risk category. In the entire study cohort, there were 1446 participants with a major vascular event, 1269 of which were major coronary events. In assessing the benefit of evolocumab by genetic risk categories, the hazard ratios (95% CI) for major vascular events in the low-, intermediate-, and high-genetic-risk categories were 0.92, 0.91, and 0.69, respectively. For those individuals without multiple clinical risk factors or high genetic risk, there was no benefit noted over a median of 2.3 years. In individuals with multiple clinical risk factors but without high genetic risk, there was a 13% relative risk reduction and 1.4% absolute risk reduction in major vascular events. For those with high genetic risk (irrespective of major clinical risk factors) there was a 31% relative risk reduction and 4.0% absolute risk reduction. There was no significant difference for the ARR across clinical risk factor burden in the high-genetic-risk category for either major vascular events or major coronary events. Study participants were divided into categories based on percentile relative to the study population, not a healthy reference population, which may have led to individuals with higher genetic risk moved into lower risk categories. Given that participants enrolled into the FOURIER trial were already candidates for intensive lipid lowering therapy, the added clinical utility of polygenic risk scoring is uncertain.

A 2022 cohort study by Joo and colleagues looked at whether genome-wide polygenic scores for psychiatric disorders and common traits were associated with the risk of suicidal thoughts among preadolescent children (age 9-10 years old). The authors analyzed data from the cohort of the Adolescent Brain and Cognitive Development (ABCD) study. In order to generate genome-wide polygenic scores, the authors used 24 psychiatric and common traits known to be associated with suicidal thoughts and behaviors. There were 6592 children included in the primary analysis (5374 of whom had only European ancestry). There were 935 children with suicidal thoughts or behaviors and 5657 children without suicidal thoughts or behaviors (the control group). Overall, the authors found genome-wide polygenic scores for attention-deficit hyperactivity disorder (ADHD) had the most significant association with phenotypes for suicidal thoughts and behaviors, with associations also found for schizophrenia and general happiness. For those in the European ancestry only group, three additional genome-wide polygenic scores were found to be associated with suicidal thoughts and behaviors: autism spectrum disorder, major depressive disorder, and posttraumatic stress disorder. While this cohort study results highlight the potential utility of genome-wide polygenic scores, further development of screening methods and intervention strategies for children at risk of suicide are necessary.

While polygenic risk scores can explain relative risk for a disease, prospective data is needed to assess whether risk identification resulting in therapeutic decision-making leads to net health outcomes. Current studies also lack generalizability.

Background/Overview

Genetic Testing Using Panels of Genes
NGS addresses any of the technologies that allow rapid sequencing of large numbers of segments of DNA, up to and including entire genomes. NGS is not a specific sequencing technology or a test in itself. Instead, the term emphasizes the difference between the earlier testing methods that involved the sequencing of one DNA strand at a time. NGS includes but is not limited to massively parallel sequencing and microarray analysis.

NGS has led to the development of genetic testing incorporating panels which analyze multiple genes for multiple mutations simultaneously. Genetic testing using panels of genes may identify numerous genetic mutations that may contribute to the development of hereditary cancers.

Commercially available genetic testing panels for breast and/or ovarian cancers include, but are not limited to: BreastNext® (Ambry Genetics®); OvaNext® (Ambry Genetics®); BREVAGen (Phenogen Sciences); and myRisk Hereditary Cancer test (Myriad Genetics).

The ColoNext test (manufactured by Ambry Genetics) is an example that tests for variants in 14 genes that have been associated with hereditary colorectal cancer, including the genes that cause Lynch syndrome (MLH1, MSH2, MSH6, PMS2 and EPCAM) as well as the gene that causes FAP (APC).

Whole Genome Sequencing
WGS, also known as full genome sequencing (FGS), complete genome sequencing, or entire genome sequencing, is a laboratory procedure which seeks to determine an individual's entire DNA sequence, specifying the order of every base pair within the genome at a single time. The role of WGS in the clinical setting has yet to be established.

Whole Exome Sequencing
While similar to WGS, WES reads only the parts of the human genome that encode proteins. Since most of the errors that occur in DNA sequences that then lead to genetic disorders are located in the exons, sequencing of the exome is being explored as a more efficient method of analyzing an individual's DNA to discover the genetic cause of diseases or disabilities. Various applications of WES are being explored including but not limited to determining if sequencing of the human exome can be used to identify genetic variants in individuals in order to diagnose diseases in individuals without the processing complexity associated with WGS.

Molecular Profiling
The rationale for molecular profiling is that more complete knowledge of molecular marker status may alter treatment and possibly improve individual outcomes. Molecular profiling refers to the analysis of DNA, RNA and/or proteins within the tumor cells. The term “molecular profiling” was initially limited to DNA analysis, but has now expanded to include analyses of RNA and proteins as well. Examples of commercially available multiple molecular testing panels are listed above. At this, only use of molecular profiling as a means of assessing tumor mutation burden has been established as a means of identifying candidates for targeted drug therapy.

Polygenic Risk Score
A polygenic risk score is a way for individuals to learn about their risk of developing a disease based on the total number of changes related to the disease. Some diseases can be traced to a variant in a single gene, while other diseases can occur due to variants in multiple genes. These variants can be identified by comparing the genomes of individuals with and without the disease. Using a computerized algorithm and statistics, a number or score is created to estimated how the collection of an individual’s variants affect risk for a certain disease.

Definitions

Ashkenazi Jewish: Persons related to Jewish settlers of the Rhine Valley in Germany and France in the middle ages.

Cancer Moonshot: A collaborative effort between the public and private sectors (including but not limited to the governments, researchers, healthcare providers, data and technology experts, patients, families, and patient advocates) to make a decade’s worth of advances in the understanding, prevention, diagnosis, treatment, and care of cancer.

Checkpoint Inhibition Immunotherapy (or Checkpoint Inhibitors): A type of drug (monoclonal antibody) that blocks certain proteins produced by immune T cells and cancer cells that keep the immune system in check and prevent the T cells from attacking cancer cells. By blocking these proteins, checkpoint inhibitors thus unleash the immune T cells to kill the cancer cells. The following is a list of FDA-approved checkpoint inhibitor drugs.

Copy number variant: An alteration of the DNA of a genome that results in the cell having an abnormal number of copies of one or more sections of the DNA.

Exome: All the exons in a genome.

Gene panel: When five or more genes are tested on the same day on the same member by the same rendering provider.

Genetic testing: A type of test that is used to determine the presence or absence of a specific gene or set of genes to help diagnose a disease, screen for specific health conditions, and for other purposes.

Genome: An organism's entire set of DNA.

Genomic data: Information derived from the sequencing of DNA or RNA fragments.

Genotype: The genetic structure (constitution) of an organism or cell.

Immunohistochemistry: The process of detecting proteins in the cells of a tissue section.

Indel: A genomic insertion or deletion.

Messenger ribonucleic acid (mRNA): A molecule that results when a cell "reads" a DNA strand.

Molecular profiling services: Laboratory services which catalogue a number of genetic markers in an attempt to select optimal therapy.

Next-generation sequencing: Any of the technologies that allow rapid sequencing of large numbers of segments of DNA, up to and including entire genomes.

Panel testing: Involves the analysis of multiple genes for multiple mutations simultaneously.

Polygenic risk score: A way to learn about the risk of developing a disease based on the total number of changes related to the disease.

Tumor mutation burden: A biomarker used to assess responsiveness to immunotherapy by measuring the total number of mutations per coding area of a tumor genome. Tumor mutation burden is typically determined by molecular (genomic) profiling with a large multigene assay/panel.

Whole-exome sequencing: Reads only the parts of the human genome that encode proteins, leaving the other regions of the genome unread.

Whole genome sequencing: A laboratory procedure which seeks to determine an individual's entire DNA sequence, specifying the order of every base pair within the genome at a single time.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Gene panel testing for inherited diseases
When services may be Medically Necessary when criteria are met:

CPT

 

81412

Ashkenazi Jewish associated disorders (eg, Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, Fanconi anemia group C, Gaucher disease, Tay-Sachs disease), genomic sequence analysis panel, must include sequencing of at least 9 genes, including ASPA, BLM, CFTR, FANCC, GBA, HEXA, IKBKAP, MCOLN1, and SMPD1

81434

Hereditary retinal disorders (eg, retinitis pigmentosa, Leber congenital amaurosis, cone-rod dystrophy), genomic sequence analysis panel, must include sequencing of at least 15 genes, including ABCA4, CNGA1, CRB1, EYS, PDE6A, PDE6B, PRPF31, PRPH2, RDH12, RHO, RP1, RP2, RPE65, RPGR, and USH2A

 

 

ICD-10 Diagnosis

 

 

All diagnoses

When services are Not Medically Necessary
For the procedure codes listed above when criteria are not met, for the following codes, or when the code describes a procedure indicated in the Position Statement section as not medically necessary.

CPT

 

 

81410

Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); genomic sequence analysis panel, must include sequencing of at least 9 genes, including FBN1, TGFBR1, TGFBR2, COL3A1, MYH11, ACTA2, SLC2A10, SMAD3, and MYLK

 

81411

Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); duplication/deletion analysis panel, must include analyses for TGFBR1, TGFBR2, MYH11, and COL3A1

 

81413

Cardiac ion channelopathies (eg, Brugada syndrome, long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia); genomic sequence analysis panel, must include sequencing of at least 10 genes, including ANK2, CASQ2, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1, RYR2, and SCN5A

 

81419

Epilepsy genomic sequence analysis panel, must include analyses for ALDH7A1, CACNA1A, CDKL5, CHD2, GABRG2, GRIN2A, KCNQ2, MECP2, PCDH19, POLG, PRRT2, SCN1A, SCN1B, SCN2A, SCN8A, SLC2A1, SLC9A6, STXBP1, SYNGAP1, TCF4, TPP1, TSC1, TSC2, and ZEB2

 

81430

Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); genomic sequence analysis panel, must include sequencing of at least 60 genes, including CDH23, CLRN1, GJB2, GPR98, MTRNR1, MYO7A, MYO15A, PCDH15, OTOF, SLC26A4, TMC1, TMPRSS3, USH1C, USH1G, USH2A, and WFS1

 

81431

Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); duplication/deletion analysis panel, must include copy number analyses for STRC and DFNB1 deletions in GJB2 and GJB6 genes

 

81440

Nuclear encoded mitochondrial genes (eg, neurologic or myopathic phenotypes), genomic sequence panel, must include analysis of at least 100 genes, including BCS1L, C10orf2, COQ2, COX10, DGUOK, MPV17, OPA1, PDSS2, POLG, POLG2, RRM2B, SCO1, SCO2, SLC25A4, SUCLA2, SUCLG1, TAZ, TK2, and TYMP

 

81442

Noonan spectrum disorders (eg, Noonan syndrome, cardio-facio-cutaneous syndrome, Costello syndrome, LEOPARD syndrome, Noonan-like syndrome), genomic sequence analysis panel, must include sequencing of at least 12 genes, including BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2, and SOS1

 

81443

Genetic testing for severe inherited conditions (eg, cystic fibrosis, Ashkenazi Jewish-associated disorders [eg, Bloom syndrome, Canavan disease, Fanconi anemia type C, mucolipidosis type VI, Gaucher disease, Tay-Sachs disease], beta hemoglobinopathies, phenylketonuria, galactosemia), genomic sequence analysis panel, must include sequencing of at least 15 genes (eg, ACADM, ARSA, ASPA, ATP7B, BCKDHA, BCKDHB, BLM, CFTR, DHCR7, FANCC, G6PC, GAA, GALT, GBA, GBE1, HBB, HEXA, IKBKAP, MCOLN1, PAH)

 

81448

Hereditary peripheral neuropathies (eg, Charcot-Marie-Tooth, spastic paraplegia), genomic sequence analysis panel, must include sequencing of at least 5 peripheral neuropathy-related genes (eg, BSCL2, GJB1, MFN2, MPZ, REEP1, SPAST, SPG11, SPTLC1)

 

81470

X-linked intellectual disability (XLID) (eg, syndromic and non-syndromic XLID); genomic sequence analysis panel, must include sequencing of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, and SLC16A2

 

81471

X-linked intellectual disability (XLID) (eg, syndromic and non-syndromic XLID); duplication/deletion gene analysis, must include analysis of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, and SLC16A2

81479

Unlisted molecular pathology procedure [when specified as an inherited disease gene panel that does not meet the medically necessary criteria, such as the following:
Counsyl, GeneVu, GoodStart Select, Inherigen, Inheritest Carrier Screen, Natera Horizon]

81599

Unlisted multianalyte assay with algorithmic analysis [when specified as a gene panel for inherited disease other than those listed as medically necessary]

0216U

Neurology (inherited ataxias), genomic DNA sequence analysis of 12 common genes including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants
Genomic Unity® Ataxia Repeat Expansion and Sequence Analysis, Variantyx Inc, Variantyx Inc

0217U

Neurology (inherited ataxias), genomic DNA sequence analysis of 51 genes including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants
Genomic Unity® Comprehensive Ataxia Repeat Expansion and Sequence Analysis, Variantyx Inc, Variantyx Inc

0237U

Cardiac ion channelopathies (eg, Brugada syndrome, long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia), genomic sequence analysis panel including ANK2, CASQ2, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1, RYR2, and SCN5A, including small sequence changes in exonic and intronic regions, deletions, duplications, mobile element insertions, and variants in non-uniquely mappable regions
Genomic Unity® Cardiac Ion Channelopathies Analysis, Variantyx Inc, Variantyx Inc

0268U

Hematology (atypical hemolytic uremic syndrome [aHUS]), genomic sequence analysis of 15 genes, blood, buccal swab, or amniotic fluid
Versiti aHUS Genetic Evaluation, Versiti Diagnostic Laboratories, Versiti

0269U

Hematology (autosomal dominant congenital thrombocytopenia), genomic sequence analysis of 14 genes, blood, buccal swab, or amniotic fluid
Versiti Autosomal Dominant Thrombocytopenia Panel, Versiti Diagnostic Laboratories, Versiti

0270U

Hematology (congenital coagulation disorders), genomic sequence analysis of 20 genes, blood, buccal swab, or amniotic fluid
Versiti Coagulation Disorder Panel, Versiti Diagnostic Laboratories, Versiti

0271U

Hematology (congenital neutropenia), genomic sequence analysis of 23 genes, blood, buccal swab, or amniotic fluid
Versiti Congenital Neutropenia Panel, Versiti Diagnostic Laboratories, Versiti

0272U

Hematology (genetic bleeding disorders), genomic sequence analysis of 51 genes, blood, buccal swab, or amniotic fluid, comprehensive
Versiti Comprehensive Bleeding Disorder Panel, Versiti Diagnostic Laboratories, Versiti

0273U

Hematology (genetic hyperfibrinolysis, delayed bleeding), genomic sequence analysis of 8 genes (F13A1, F13B, FGA, FGB, FGG, SERPINA1, SERPINE1, SERPINF2, PLAU), blood, buccal swab, or amniotic fluid
Versiti Fibrinolytic Disorder Panel, Versiti Diagnostic Laboratories, Versiti

0274U

Hematology (genetic platelet disorders), genomic sequence analysis of 43 genes, blood, buccal swab, or amniotic fluid
Versiti Comprehensive Platelet Disorder Panel, Versiti Diagnostic Laboratories, Versiti

0276U

Hematology (inherited thrombocytopenia), genomic sequence analysis of 42 genes, blood, buccal swab, or amniotic fluid
Versiti Inherited Thrombocytopenia Panel, Versiti Diagnostic Laboratories, Versiti

0277U

Hematology (genetic platelet function disorder), genomic sequence analysis of 31 genes, blood, buccal swab, or amniotic fluid
Versiti Platelet Function Disorder Panel, Versiti Diagnostic Laboratories, Versiti

0278U

Hematology (genetic thrombosis), genomic sequence analysis of 12 genes, blood, buccal swab, or amniotic fluid
Versiti Thrombosis Panel, Versiti Diagnostic Laboratories, Versiti

 

 

ICD-10 Diagnosis

 

  All diagnoses

Gene Panel Testing for Cancer Susceptibility and Management
When services may be Medically Necessary when criteria are met:

CPT

 

81432

Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); genomic sequence analysis panel, must include sequencing of at least 10 genes, always including BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, PALB2, PTEN, STK11, and TP53 [for breast cancer testing of less than 51 genes and when genes ATM, BARD1, CHEK2, RAD51C, and RAD51D are also included]

81433

Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); duplication/deletion analysis panel, must include analyses for BRCA1, BRCA2, MLH1, MSH2, and STK11 [for breast cancer testing of less than 51 genes and when genes ATM, BARD1, CHEK2, PALB2, RAD51C, and RAD51D are also included]

81435

Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include sequencing of at least 10 genes, including APC, BMPR1A, CDH1, MLH1, MSH2, MSH6, MUTYH, PTEN, SMAD4, and STK11 [for Lynch syndrome testing of less than 51 genes and when genes EPCAM and PMS2 are also included]

81436

Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); duplication/deletion analysis panel, must include analysis of at least 5 genes including MLH1, MSH2, EPCAM, SMAD4, and STK11 [for Lynch syndrome testing of less than 51 genes and when genes MSH6 and PMS2 are also included]

81445

Targeted genomic sequence analysis panel, solid organ neoplasm, DNA analysis, and RNA analysis when performed, 5-50 genes (eg, ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed [when specified as one of the following]:

  • Breast cancer panel test including at a minimum ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, and RAD51D genes
  • Lynch Syndrome panel test including at a minimum EPCAM, MLH1, MSH2, MSH6, and PMS2 genes
  • NSCLC panel test including at a minimum ALK, BRAF, EGFR, ERBB2 (HER2), KRAS, MET, NTRK, RET and ROS1 genes
  • Prostate cancer panel to evaluate deleterious germline or somatic homologous recombination repair (HRR) genes (eg, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L)

81450

Targeted genomic sequence analysis panel, hematolymphoid neoplasm or disorder, DNA analysis, and RNA analysis when performed, 5-50 genes (eg, BRAF, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KRAS, KIT, MLL, NRAS, NPM1, NOTCH1), interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed [when specified as one of the following]:

  • Acute lymphoblastic leukemia (ALL) panel test including at a minimum ABL1, ABL2, CRLF2, CSF1R, FLT3, IL7R, JAK1, JAK2, JAK3, PDGFRB, and SH2B3 genes
  • Acute myeloid leukemia (AML) panel test including at a minimum ASXL1, BCR-ABL, c-KIT, CEBPA (biallelic), FLT3-ITD, FLT3-TKD, IDH1, IDH2, NPM1, PML-RAR alpha, RUNX1, and TP53 genes
  • Myelodysplastic syndrome (MDS) panel test including at a minimum ASXL1, DNMT3A, EZH2, NRAS, RUNX1, SF3B1, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2 genes

81479

Unlisted molecular pathology procedure [when specified as one of the following panels:

  • Acute lymphoblastic leukemia (ALL) 5-50 gene panel, including at a minimum ABL1, ABL2, CRLF2, CSF1R, FLT3, IL7R, JAK1, JAK2, JAK3, PDGFRB, and SH2B3 genes
  • Acute myeloid leukemia (AML) 5-50 gene panel, including at a minimum ASXL1, BCR-ABL, c-KIT, CEBPA (biallelic), FLT3-ITD, FLT3-TKD, IDH1, IDH2, NPM1, PML-RAR alpha, RUNX1, and TP53 genes
  • Breast cancer 5-50 gene panel, including at a minimum ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, and RAD51D genes
  • Lynch Syndrome 5-50 gene panel, including at a minimum EPCAM, MLH1, MSH2, MSH6, and PMS2 genes
  • Myelodysplastic syndrome (MDS) 5-50 gene panel, including at a minimum ASXL1, DNMT3A, EZH2, NRAS, RUNX1, SF3B1, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2 genes
  • NSCLC 5-50 gene panel, including at a minimum ALK, BRAF, EGFR, ERBB2 (HER2), KRAS, MET, NTRK, RET and ROS1 genes
  • Prostate cancer 5-50 gene panel to evaluate deleterious germline or somatic homologous recombination repair (HRR) genes (eg, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L)

0101U

Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis), genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA, and array CGH, with MRNA analytics to resolve variants of unknown significance when indicated (15 genes [sequencing and deletion/duplication], EPCAM and GREM1 [deletion/duplication only])
ColoNext®, Ambry Genetics®, Ambry Genetics®

0102U

Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA, and array CGH, with MRNA analytics to resolve variants of unknown significance when indicated (17 genes [sequencing and deletion/duplication])
BreastNext®, Ambry Genetics®, Ambry Genetics®

0103U

Hereditary ovarian cancer (eg, hereditary ovarian cancer, hereditary endometrial cancer), genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA, and array CGH, with MRNA analytics to resolve variants of unknown significance when indicated (24 genes [sequencing and deletion/duplication], EPCAM [deletion/duplication only])
OvaNext®, Ambry Genetics®, Ambry Genetics®

0238U

Oncology (Lynch syndrome), genomic DNA sequence analysis of MLH1, MSH2, MSH6, PMS2, and EPCAM, including small sequence changes in exonic and intronic regions, deletions, duplications, mobile element insertions, and variants in non-uniquely mappable regions
Genomic Unity® Lynch Syndrome Analysis, Variantyx Inc, Variantyx Inc

 

 

ICD-10 Diagnosis

 

 

All diagnoses

When services are Not Medically Necessary
For the procedure codes listed above when criteria are not met, for the following codes, or when the code describes a procedure indicated in the Position Statement section as not medically necessary.

CPT

 

81437

Hereditary neuroendocrine tumor disorders (eg, medullary thyroid carcinoma, parathyroid carcinoma, malignant pheochromocytoma or paraganglioma); genomic sequence analysis panel, must include sequencing of at least 6 genes, including MAX, SDHB, SDHC, SDHD, TMEM127, and VHL

81438

Hereditary neuroendocrine tumor disorders (eg, medullary thyroid carcinoma, parathyroid carcinoma, malignant pheochromocytoma or paraganglioma); duplication/deletion analysis panel, must include analyses for SDHB, SDHC, SDHD, and VHL

81455

Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA analysis, and RNA analysis when performed, 51 or greater genes (eg, ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed

81479

Unlisted molecular pathology procedure [when specified as a gene panel that does not meet medically necessary criteria]

81599

Unlisted multianalyte assay with algorithmic analysis [when specified as a gene panel that does not meet medically necessary criteria]

0050U

Targeted genomic sequence analysis panel, acute myelogenous leukemia, DNA analysis, 194 genes, interrogation for sequence variants, copy number variants or rearrangements
MyAML NGS Panel; LabPMM LLC, an Invivoscribe Technologies, Inc. Company

0129U

Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), genomic sequence analysis and deletion/duplication analysis panel (ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, and TP53)
BRCAplus, Ambry Genetics

0130U

Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis), targeted mRNA sequence analysis panel (APC, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, and TP53)
+RNAinsight for ColoNext®, Ambry Genetics

0131U

Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), targeted mRNA sequence analysis panel (13 genes)
+RNAinsight for BreastNext®, Ambry Genetics

0132U

Hereditary ovarian cancer–related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), targeted mRNA sequence analysis panel (17 genes)
+RNAinsight for OvaNext®, Ambry Genetics

0134U

Hereditary pan cancer (eg, hereditary breast and ovarian cancer, hereditary endometrial cancer, hereditary colorectal cancer), targeted mRNA sequence analysis panel (18 genes)
+RNAinsight for CancerNext®, Ambry Genetics

0135U

Hereditary gynecological cancer (eg, hereditary breast and ovarian cancer, hereditary endometrial cancer, hereditary colorectal cancer), targeted mRNA sequence analysis panel (12 genes)
+RNAinsight for GYNPlus®, Ambry Genetics

0343U

Oncology (prostate), exosome-based analysis of 442 small noncoding RNAs (sncRNAs) by quantitative reverse transcription polymerase chain reaction (RT-qPCR), urine, reported as molecular evidence of no-, low-, intermediate- or high-risk of prostate cancer
miR Sentinel Prostate Cancer Test, miR Scientific, LLC, miR Scientific, LLC

 

 

ICD-10 Diagnosis

 

 

All diagnoses

Whole Exome Sequencing
When services may be Medically Necessary when criteria are met:

CPT

 

81415

Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis

81416

Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator exome (eg, parents, siblings)

81417

Exome (eg, unexplained constitutional or heritable disorder or syndrome); re-evaluation of previously obtained exome sequence (eg, updated knowledge or unrelated condition/syndrome)

0214U

Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, proband
Genomic Unity® Exome Plus Analysis - Proband, Variantyx Inc, Variantyx Inc

0215U

Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, each comparator exome (eg, parent, sibling)
Genomic Unity® Exome Plus Analysis - Comparator, Variantyx Inc, Variantyx Inc

 

 

ICD-10 Diagnosis

 

 

All diagnoses

When services are Not Medically Necessary
For the procedure codes listed above when criteria are not met, for the following procedure code, or when the code describes a procedure indicated in the Position Statement section as not medically necessary.

CPT

 

0036U

Exome (ie, somatic mutations), paired formalin-fixed paraffin-embedded tumor tissue and normal specimen, sequence analyses
EXaCT-1 Whole Exome Testing; Lab of Oncology-Molecular Detection, Weill Cornell Medicine Clinical Genomics Laboratory

 

 

ICD-10-Diagnosis

 

 

All diagnoses

Molecular profiling
When services may be Medically Necessary when criteria are met:

CPT

 

 

Including, but not limited to, the following:

0037U

Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden
FoundationOne CDx (F1CDx); Foundation Medicine, Inc.

0048U

Oncology (solid organ neoplasia), DNA, targeted sequencing of protein-coding exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s)
MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets); Memorial Sloan Kettering Cancer Center

0211U

Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association
MI Cancer Seek - NGS Analysis, Caris MPI d/b/a Caris Life Sciences, Caris MPI d/b/a Caris Life Sciences

0244U

Oncology (solid organ), DNA, comprehensive genomic profiling, 257 genes, interrogation for single-nucleotide variants, insertions/deletions, copy number alterations, gene rearrangements, tumor-mutational burden and microsatellite instability, utilizing formalin-fixed paraffin-embedded tumor tissue
Oncotype MAP PanCancer Tissue Test, Paradigm Diagnostics, Inc, Paradigm Diagnostics, Inc

0250U

Oncology (solid organ neoplasm), targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations (SNVs [single nucleotide variant], small insertions and deletions, one amplification, and four translocations), microsatellite instability and tumor-mutation burden
PGDx elio tissue complete, Personal Genome Diagnostics, Inc, Personal Genome Diagnostics, Inc

0329U

Oncology (neoplasia), exome and transcriptome sequence analysis for sequence variants, gene copy number amplifications and deletions, gene rearrangements, microsatellite instability and tumor mutational burden utilizing DNA and RNA from tumor with DNA from normal blood or saliva for subtraction, report of clinically significant mutation(s) with therapy associations
Oncomap ExTra; Exact Sciences; Genomic Health, Inc.

0334U

Oncology (solid organ), targeted genomic sequence analysis, formalin-fixed paraffin-embedded (FFPE) tumor tissue, DNA analysis, 84 or more genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden
Guardant360 TissueNext, Guardant Health, Inc, Guardant Health, Inc

 

 

ICD-10 Diagnosis

 

C00.0-C80.2

Malignant neoplasms

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed, for the following procedure codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT

 

81479

Unlisted molecular pathology procedure [when specified as a molecular profiling panel that does not meet medically necessary criteria]

81599

Unlisted multianalyte assay with algorithmic analysis [when specified as a molecular profiling panel that does not meet medically necessary criteria]

 

 

ICD-10 Diagnosis

 

 

All diagnoses

Other panels (Whole Genome, Whole Transcriptome, Polygenic Risk Scoring,
When services are Investigational and Not Medically Necessary:
For the following codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT

 

 

81425

Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis

 

81426

Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator exome (eg, parents, siblings)

 

81427

Genome (eg, unexplained constitutional or heritable disorder or syndrome); re-evaluation of previously obtained genome sequence (eg, updated knowledge or unrelated condition/syndrome)

 

81460

Whole mitochondrial genome (eg, Leigh syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS], myoclonic epilepsy with ragged-red fibers [MERFF], neuropathy, ataxia, and retinitis pigmentosa [NARP], Leber hereditary optic neuropathy [LHON]), genomic sequence, must include sequence analysis of entire mitochondrial genome with heteroplasmy detection

 

81465

Whole mitochondrial genome large deletion analysis panel (eg, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia), including heteroplasmy detection if performed

 

81479

Unlisted molecular pathology procedure [when specified as a whole genome, whole transcriptome or polygenic risk score test]

81599

Unlisted multianalyte assay with algorithmic analysis [when specified as a whole genome, whole transcriptome or polygenic risk score test]

0094U

Genome (eg, unexplained constitutional or heritable disorder or syndrome), rapid sequence analysis
RCIGM Rapid Whole Genome Sequencing, Rady Children's Institute for Genomic Medicine (RCIGM)

0212U

Rare diseases (constitutional/heritable disorders), whole genome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, proband
Genomic Unity® Whole Genome Analysis - Proband, Variantyx Inc, Variantyx Inc

0213U

Rare diseases (constitutional/heritable disorders), whole genome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, each comparator genome (eg, parent, sibling)
Genomic Unity® Whole Genome Analysis - Comparator, Variantyx Inc, Variantyx Inc

0260U

Rare diseases (constitutional/heritable disorders), identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping
Augusta Optical Genome Mapping, Georgia Esoteric and Molecular (GEM) Laboratory, LLC, Bionano Genomics Inc

0264U

Rare diseases (constitutional/heritable disorders), identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping
Praxis Optical Genome Mapping, Praxis Genomics LLC

0265U

Rare constitutional and other heritable disorders, whole genome and mitochondrial DNA sequence analysis, blood, frozen and formalin-fixed paraffin embedded (FFPE) tissue, saliva, buccal swabs or cell lines, identification of single nucleotide and copy number variants
Praxis Whole Genome Sequencing, Praxis Genomics LLC

0266U

Unexplained constitutional or other heritable disorders or syndromes, tissue specific gene expression by whole transcriptome and next-generation sequencing, blood, formalin-fixed paraffin embedded (FFPE) tissue or fresh frozen tissue, reported as presence or absence of splicing or expression changes
Praxis Transcriptome, Praxis Genomics LLC

0267U

Rare constitutional and other heritable disorders, identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping and whole genome sequencing
Praxis Combined Whole Genome Sequencing and Optical Genome Mapping, Praxis Genomics LLC

0297U

Oncology (pan tumor), whole genome sequencing of paired malignant and normal DNA specimens, fresh or formalin-fixed paraffin-embedded (FFPE) tissue, blood or bone marrow, comparative sequence analyses and variant identification
Praxis Somatic Whole Genome Sequencing, Praxis Genomics LLC

0298U

Oncology (pan tumor), whole transcriptome sequencing of paired malignant and normal RNA specimens, fresh or formalin-fixed paraffin-embedded (FFPE) tissue, blood or bone marrow, comparative sequence analyses and expression level and chimeric transcript identification
Praxis Somatic Transcriptome, Praxis Genomics LLC

0299U

Oncology (pan tumor), whole genome optical genome mapping of paired malignant and normal DNA specimens, fresh frozen tissue, blood, or bone marrow, comparative structural variant identification
Praxis Somatic Optical Genome Mapping, Praxis Genomics LLC

0300U

Oncology (pan tumor), whole genome sequencing and optical genome mapping of paired malignant and normal DNA specimens, fresh tissue, blood, or bone marrow, comparative sequence analyses and variant identification
Praxis Somatic Combined Whole Genome Sequencing and Optical Genome Mapping, Praxis Genomics LLC

0331U

Oncology (hematolymphoid neoplasia), optical for copy number alterations and gene rearrangements utilizing DNA from blood or bone marrow, report of clinically significant alternations
Augusta Hematology Optical Genome Mapping; Bionano Genomics

0335U

Rare diseases (constitutional/heritable disorders), whole genome sequence analysis, including small sequence changes, copy number variants, deletions, duplications, mobile element insertions, uniparental disomy (UPD), inversions, aneuploidy, mitochondrial genome sequence analysis with heteroplasmy and large deletions, short tandem repeat (STR) gene expansions, fetal sample, identification and categorization of genetic variants
IriSight Prenatal Analysis – Proband, Variantyx, Inc, Variantyx, Inc

0336U

Rare diseases (constitutional/heritable disorders), whole genome sequence analysis, including small sequence changes, copy number variants, deletions, duplications, mobile element insertions, uniparental disomy (UPD), inversions, aneuploidy, mitochondrial genome sequence analysis with heteroplasmy and large deletions, short tandem repeat (STR) gene expansions, blood or saliva, identification and categorization of genetic
variants, each comparator genome (eg, parent)
IriSight Prenatal Analysis – Comparator, Variantyx, Inc, Variantyx, Inc

 

 

ICD-10 Diagnosis

 

  All diagnoses
References

Peer Reviewed Publications:

  1. Beltran H, Eng K, Mosquera JM, et al. Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response. JAMA Oncol. 2015; 1(4):466-474.
  2. Beltran H, Yelensky R, Frampton GM. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur Urol. 2013; 63(5):920-926.
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  10. Drilon A, Wang L, Hasanovic A. Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. 2013; 3(6):630-635.
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  14. Grzymski JJ, Elhanan G, Morales Rosado JA, et al. Population genetic screening efficiently identifies carriers of autosomal dominant diseases. Nat Med. 2020; 26(8):1235-1239.
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  21. Joo YY, Moon SY, Wang HH, et al. Association of genome-wide polygenic scores for multiple psychiatric and common traits in preadolescent youths at risk of suicide. JAMA Netw Open. 2022; 5(2):e2148585.
  22. Krantz ID, Medne L, Weatherly JM, et al. Effect of whole-genome sequencing on the clinical management of acutely ill infants with suspected genetic disease: a randomized clinical trial. JAMA Pediatr. 2021; 175(12):1218-1226.
  23. LaDuca H, Stuenkel AJ, Dolinsky JS, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med. 2014; 16(11):830-837.
  24. Le Tourneau C, Delord JP, Gonçalves A, et al.; SHIVA Investigators. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol. 2015; 16(13):1324-1334.
  25. Le Tourneau C, Kamal M, Trédan O, et al. Designs and challenges for personalized medicine studies in oncology: focus on the SHIVA trial. Target Oncol. 2012; 7(4):253-265.
  26. Lincoln SE, Kobayashi Y, Anderson MJ, et al. A systematic comparison of traditional and multigene panel testing for hereditary breast and ovarian cancer genes in more than 1000 patients. J Mol Diagn. 2015; 17(5):533-544.
  27. Lipson D, Capelletti M, Yelensky R. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012; 18(3):382-384.
  28. Lord J, McMullan DJ, Eberhardt RY, et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet 2019; 393(10173):747-757.
  29. Mandelker D, Zhang L, Kemel Y, et al. Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing. JAMA. 2017; 318(9):825-835.
  30. Marston NA, Kamanu FK, Nordio F, et al. Predicting benefit from evolocumab therapy in patients with atherosclerotic disease using a genetic risk score: results from the FOURIER trial. Circulation. 2020; 141(8):616-623.
  31. Mukherjee S, Ma Z, Wheeler S, et al. Chromosomal microarray provides enhanced targetable gene aberration detection when paired with next generation sequencing panel in profiling lung and colorectal tumors. Cancer Genet. 2016; 209(4):119-129.
  32. Petrovski S, Aggarwal V, Giordano JL, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet. 2019; 393(10173):758-767.
  33. Pishvaian MJ, Blais EM, Brody JR, et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol . 202; 21(4):508-518.
  34. Presley CJ, Tang D, Soulos PR, et al. Association of broad-based genomic sequencing with survival among patients with advanced non-small cell lung cancer in the community oncology setting. JAMA. 2018; 320(5):469-477.
  35. Ross JS, Ali SM, Wang K. Comprehensive genomic profiling of epithelial ovarian cancer by next generation sequencing-based diagnostic assay reveals new routes to targeted therapies. Gynecol Oncol. 2013a; 130(3):554-559.
  36. Ross JS, Wang K, Sheehan CE. Relapsed classic E-cadherin (CDH1)-mutated invasive lobular breast cancer shows a high frequency of HER2 (ERBB2) gene mutations. Clin Cancer Res. 2013b; 19(10):2668-2676.
  37. Sparks TN, Lianoglou BR, Adami RR, et al. Exome sequencing for prenatal diagnosis in nonimmune hydrops fetalis. N Engl J Med. 2020; 383:1746-1756.
  38. Susswein LR, Marshall ML, Nusbaum R, et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016; 18(8):823-832.
  39. Teer JK, Bonnycastle LL, Chines PS, et al. Systematic comparison of three genomic enrichment methods for massively parallel DNA sequencing. Genome Res. 2010(a) 20(10):1420-1431.
  40. Teer JK, Mullikin JC. Exome sequencing: the sweet spot before whole genomes. Hum Mol Genet. 2010(b) 19(R2):R145-151.
  41. Teer JK, Zhang Y, Chen L, et al. Evaluating somatic tumor mutation detection without matched normal samples. Hum Genomics. 2017; 11(1):22.
  42. Tsimberidou AM, Iskander NG, Hong DS, et al. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clin Cancer Res. 2012; 18(22):6373-6383.
  43. Tung N, Battelli C, Allen B, et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015; 121(1):25-33.
  44. Vignot S, Frampton GM, Soria JC. Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer. J Clin Oncol. 2013; 31(17):2167-2172.
  45. Von Hoff DD, Stephenson JJ Jr., Rosen P, et al. Pilot study using molecular profiling of patients' tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010; 28(33):4877-4883.
  46. Westemeyer M, Saucier J, Wallace J, et al. Clinical experience with carrier screening in a general population: support for a comprehensive pan-ethnic approach. Genet Med. 2020; 22(8):1320-1328.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. ACMG Board of Directors. Points to consider in the clinical application of genomic sequencing. Genet Med. 2012; 14(8):759-761.
  2. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 691: Cancer Screening for Genetic Conditions. Obstet Gynecol. 2017; 129(3):e41-e55.
  3. Centers for Medicare and Medicaid Services (CMS). National Coverage Determination: Next Generation Sequencing (NGS). NCD #90.2. Effective March 16, 2018. Available at: https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=290&SearchType=Advanced&CoverageSelection. Accessed on January 12, 2022.
  4. Committee on Genetics and the Society for Maternal-Fetal Medicine. Microarrays and Next-Generation Sequencing Technology: The use of advanced genetic diagnostic tools in obstetrics and gynecology. Obstet Gynecol. 2016; 128(6):e262-e268.
  5. Deignan JL, Astbury C, Cutting GR, et al. CFTR variant testing: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020; (8):1288-1295..
  6. Edwards JG, Feldman G, Goldberg J, et al. Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. Obstet Gynecol. 2015; 125(3):653-662.
  7. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013; 15(7):565-574.
  8. Grody WW, Thompson BH, Gregg AR, et al. ACMG position statement on prenatal/preconception expanded carrier screening. Genet Med. 2013; 15(6):482-483.
  9. Gross SJ, Pletcher BA, Monaghan KG; et al. Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med. 2008; 10(1):54-56.
  10. International Society for Prenatal Diagnosis; Society for Maternal and Fetal Medicine; Perinatal Quality Foundation. Joint Position Statement from the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis. Prenat Diagn. 2018; 38(1):6-9.
  11. Keytruda® [Product Information], Kenilworth, NJ. Merck; Updated on October 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s121s122lbl.pdf. Accessed on January 12, 2022.
  12. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: Guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018; 142(3):321-346.
  13. Lynparza® [Product Information], Gaithersburg, MD. AstraZeneca; Updated on March 11, 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208558s019s020lbl.pdf. Accessed on January 12, 2022.
  14. Manickam K, McClain MR, Demmer LA, et al. Exome and genome sequencing for pediatric patients with congenital anomalies for intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021; 23(11):2029-2037..
  15. Miller DT, Lee K, Chung WK, et al. ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. . 2021; 23(8):1381-1390.
  16. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org/index.asp. Accessed on January 12, 2022.
  17. Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology Policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015; 33:3660-3667.
  18. Stone EM, Aldave AJ, Drack AV, et al. Recommendations for genetic testing of inherited eye diseases: report of the American Academy of Ophthalmology task force on genetic testing. Ophthalmology. 2012; 119(11):2408-2410.
  19. U.S. Food and Drug Administration Premarket Approval Database. FoundationOne CDx Summary of Safety and Effectiveness. No. P170019. Rockville, MD: FDA. November 30, 2017a. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170019B.pdf. Accessed on January 12, 2022.
  20. U.S. Food and Drug Administration De Novo Database. MSK-IMPACT Decision Summary. DEN170058. Rockville, MD: FDA. November 15, 2017b. Available at: https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN170058.pdf. Accessed on January 12, 2022.
Websites for Additional Information
  1. American Cancer Society. Available at: http://www.cancer.org. Accessed on January 12, 2022.
  2. National Human Genome Research Institute. Available at: https://www.genome.gov/. Accessed on January 12, 2022.
Index

BreastNext Test
BREVAGen
Caris Life Sciences Molecular Intelligence Service
Caris Target Now
Caris Test
EXaCT-1 Whole Exome Sequencing
FoundationOne
FoundationOne CDx
GeneKey
Genetic testing panels
Genetic testing using panels
Ion Torrent Next Generation Sequencing Ion AmpliSeq
MatePair
Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)
Multi-Omic Molecular Profiling (MMP)
MyAML
myRisk Hereditary Cancer test
OmniSeq Advance
OncInsights
Oncotype MAP PanCancer Tissue Test
OvaNext Test
SmartGenomics
Target Now Molecular Profiling Service

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

 

09/28/2022

Updated Coding section with 10/01/2022 CPT changes; added 0334U, 0335U, 0336U, 0343U; revised descriptor for 0276U; removed 0012U, 0013U, 0014U and 0056U deleted 09/30/2022.

 

06/29/2022

Updated Coding section with 07/01/2022 CPT changes; added 0329U, 0331U.

Revised

02/17/2022

Medical Policy & Technology Assessment Committee (MPTAC) review. Added polygenic risk score testing to the scope as investigational and not medically necessary. Clarified criteria for Lynch syndrome to add “containing 5-50 genes” and “at a minimum.” Added MN statements for gene panel testing for initial evaluation of myelodysplastic syndromes, acute myeloid leukemia, and acute lymphoblastic leukemia. Clarified criteria for WES to clarify “live” fetus. Revised MN criteria for gene panel testing for prostate cancer to remove “Lynparza” and add “a poly (ADP-ribose)polymerase (PARP) inhibitor.” Revised INV/NMN statement for testing for gene panels and whole exome sequencing to NMN only. Updated Description/Scope, Rationale, Background/Overview, Definitions, and References sections. Updated Coding section, including removing 0171U now addressed in CG-GENE-19.

Revised

11/11/2021

MPTAC review. Added MN criteria for breast cancer susceptibility using gene panels. Added MN criteria for advanced non-small cell lung cancer using gene panels. Added MN criteria for whole exome sequencing. Updated Description/Scope, Rationale, References, and Websites for Additional Information sections. Updated Coding section to include 01/01/2022 CPT changes, added 0297U, 0298U, 0299U, 0300U.

 

10/01/2021

Updated Coding section with 10/01/2021 CPT changes; added 0260U, 0264U-0274U, 0276U-0278U.

 

07/01/2021

Updated Coding section with 07/01/2021 CPT changes; added 0250U.

Reviewed

02/11/2021

MPTAC review. Updated Description/Scope, Rationale, References, and Index sections. Updated Coding section with 04/01/2021 CPT changes; added 0244U.

Revised

11/05/2020

MPTAC review. Added MN criteria for prostate cancer using gene panels when the panel evaluates HRR repair gene alterations and an individual is a candidate for treatment with Lynparza (olaparib). Updated Rationale and Reference sections. Updated Coding section to include 01/01/2021 CPT changes to add 81419, 0237U, 0238U.

Revised

08/13/2020

MPTAC review. Removed MN indication for molecular profiling for NSCLC. Added MN indication for molecular profiling for unresectable or metastatic solid tumors. Updated Rationale and References sections. Updated Coding section to include 10/01/2020 CPT changes, added 0211U-0217U; added 81448 previously addressed in GENE.00033.

 

07/08/2020

Updated Coding section; added 81413 previously addressed in GENE.00007.

 

04/01/2020

Updated Coding section with 04/01/2020 CPT changes; added 0171U.

Revised

01/13/2020

MPTAC review. Addition to Position Statement regarding gene panel testing for Lynch Syndrome. Updated Rationale and Coding sections.

New

11/07/2019

MPTAC review. Initial document development. Moved content regarding whole genome sequencing, whole exome sequencing, gene panel tests and molecular profiling from GENE.00001 Genetic Testing for Cancer Susceptibility, GENE.00012 Preconception or Prenatal Genetic Testing of a Parent or Prospective Parent, GENE.00025 Molecular Profiling and Proteogenomic Testing for the Evaluation of Malignancies, GENE.00028 Genetic Testing for Colorectal Cancer Susceptibility, GENE.00029 Genetic Testing for Breast and/or Ovarian Cancer Syndrome, GENE.00030 Genetic Testing for Endocrine Gland Cancer Susceptibility, GENE.00035 Genetic Testing for TP53 Mutations, and GENE.00043 Genetic Testing of an Individual’s Genome for Inherited Diseases to this new medical policy document. Updated Coding section to remove 81506, not applicable.


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