Clinical UM Guideline

This document addresses genetic testing for the following types of hereditary colorectal cancer:

• Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer);
• Familial Adenomatous Polyposis (FAP);
• Attenuated FAP (AFAP); and
• MYH-associated Polyposis (MAP).

This document does not address panel testing for colorectal cancer susceptibility. Please refer to:

• GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling

For additional information on genetic testing for malignant conditions, please refer to:

• CG-GENE-14 Gene Mutation Testing for Cancer Susceptibility and Management
• CG-GENE-16 BRCA Genetic Testing

Note: Although immunohistochemistry (IHC) and microsatellite instability (MSI) are discussed in this document, this document is not meant to provide testing criteria for IHC or MSI.

Medically Necessary:

Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer [HNPCC])

1. Genetic testing for Lynch syndrome is considered medically necessary when information is available that may guide targeted testing, (that is: one of criteria A or B) and all of criteria C are met:
   1. IHC shows loss of nuclear staining for one or more of the mismatch repair enzymes and gene testing is guided by these results; or
   2. The individual has a family history of a known mutation in the MLH1, MSH2, MSH6, PMS2 or EPCAM genes; 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.
2. Genetic testing for Lynch syndrome is considered medically necessary when information that may guide targeted testing is unavailable, (that is: one of criteria A), and any one of criteria B through K and all of criteria L are met:
   1. Information that may guide targeted testing is unavailable:
      1. There are no IHC tumor testing results; or
      2. There is no family history of a known mutation in the MLH1, MSH2, MSH6, PMS2 or EPCAM genes; or
      3. The affected family member or proband is unavailable for testing; and
   2. Individual has a colorectal or endometrial cancer diagnosed prior to 50 years of age; or
   3. Individual with colorectal or endometrial cancer diagnosed at any age when there is a family history of a first-degree or second-degree relative with Lynch syndrome-related cancer^§ diagnosed prior to 50 years of age; or
   4. Individual with colorectal or endometrial cancer diagnosed at any age when there is a family history of 2 or more first-degree or second-degree relatives with Lynch syndrome-related cancer^§ diagnosed at any age; or
   5. The individual has a history of synchronous or metachronous Lynch syndrome-related tumor(s) ^§, regardless of age; or 
   6. The individual has a personal history of colorectal or endometrial cancer and the tumor shows evidence of mismatch repair deficiency (either high microsatellite instability [MSI] or loss of mismatch repair protein expression) at any age; or
   7. Individual has a predicted risk for Lynch syndrome greater than 5% on one of the following prediction models: MMRpro, PREMM or MMRpredict; or   
   8. The individual for whom the test is requested, has a first-degree relative with 2 or more Lynch syndrome-related tumors^§, including synchronous and metachronous tumors; or
   9. The individual for whom the test is requested, has 2 or more first- or second-degree relatives with a history of a Lynch syndrome-related cancer^§, including at least 1 relative which was diagnosed with a Lynch syndrome-related cancer^§ prior to age 50; or
   10. The individual for whom the test is requested, has a first-degree relative with colorectal cancer or endometrial cancer diagnosed prior to age 50; or
   11. The individual for whom the test is requested, has a family history of 3 or more first-degree or second-degree relatives with Lynch syndrome-related cancers^§, regardless of age; and
   12. 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.
          § Lynch-related tumors (cancers) include: colorectal, gastric, small bowel, endometrial, ovarian, pancreas, ureter, renal pelvis, biliary tract, brain, sebaceous gland adenomas and keratocanthomas.

Familial Adenomatous Polyposis (FAP) and Attenuated FAP (AFAP)

1. Genetic testing to detect mutations in the APC (adenomatous polyposis coli) gene is considered medically necessary when any one of criteria A through D and all of criteria E are met:
   1. Individuals with greater than 10 adenomatous colonic polyps during their lifetime; or
   2. First- or second-degree relatives of individuals diagnosed with FAP or AFAP; or
   3. First- or second-degree relatives of individuals with a known APC gene mutation; or
   4. Individuals with a personal history of a desmoid tumor; and
   5. 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.

MYH (Human MutY homolog)-associated Polyposis (MAP)

1. Genetic testing for MYH (also known as MUTYH) -associated polyposis (MAP) is considered medically necessary when either criterion A or B and all of criteria C are met:
   1. The individual has greater than 10 adenomatous colonic polyps; or
   2. The individual is asymptomatic and has a first-degree relative with known MAP mutation; 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.

Not Medically Necessary:

Genetic testing for HNPCC, FAP, AFAP or MAP is considered not medically necessary in individuals not meeting any of the criteria above.

The following codes for treatments and procedures applicable to this guideline 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.

Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer [HNPCC])
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed.

Familial Adenomatous Polyposis (FAP), Attenuated FAP (AFAP) and MYH (Human MutY homolog)-associated Polyposis (MAP)
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed.

There are multiple well-defined types of hereditary colorectal cancer (CRC); three of the most common are familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), known as Lynch syndrome, and MYH-associated Polyposis (MAP). FAP can be clinically recognized by the presence of hundreds of colon polyps, typically apparent by age 10-20. If left untreated, affected individuals will go on to develop colorectal cancer. Individuals with HNPCC tend to have early-onset colorectal cancer, right-sided tumors and/or multiple synchronous or metachronous lesions. Extracolonic tumors may also be present. The lifetime risk of developing colorectal cancer in HPNCC is approximately 80%. Germline mutations have been associated with both FAP and HNPCC creating the option of genetic testing of both affected individuals (to establish the genetic basis of the tumor) and their family members (to determine whether an individual carries the same mutation as the affected relative). Subjects with germline mutations may undergo increased surveillance or may consider prophylactic colectomy.

Lynch Syndrome (Hereditary Non-Polyposis Colon Cancer [HNPCC])

Lynch syndrome is defined as a hereditary predisposition to CRC and other malignancies including endometrial and gastric cancer. Lynch syndrome is the most common form of genetically determined colon cancer and accounts for 1-3% of all newly diagnosed CRC cases and 3% of endometrial cancers. This predisposition is a result of a mismatch repair (MMR) germ-line (constitutional) gene mutation (MLH1, MSH2, MSH6, and PMS2) or epithelial cell adhesion molecule (EPCAM, which causes epigenetic silencing of MSH2). It has been estimated that over 70% of MMR mutations are located in the MLH1, MSH2 genes, or EPCAM in tumors with microsatellite instability (MSI)-high. Pathogenic genetic alterations might be frameshift, nonsense and splice site mutations that result in truncating or unstable proteins. Large deletions and rearrangements are also common. Therefore, full germline genetic testing including both DNA sequencing and large rearrangement analysis has been recommended (Stjepanovic, 2019).

EPCAM is not an MMR gene but can disrupt the MMR pathway. Large deletions of the EPCAM gene can lead to hypermethylation of the MSH2 promoter and subsequent MSH2 silencing. It has been estimated that EPCAM deletions may account for 20-25% of cases in which MSH2 protein is not detected by IHC but germline MSH2 mutations are not identified. The National Comprehensive Cancer Network (NCCN) guidelines for Genetic/Familial High Risk Assessment: Colorectal Cancer indicate that germline mutation testing of the EPCAM gene is appropriate when the tumor IHC stain is negative (absent) for both MSH2 and MSH6 and genetic testing for MSH2 is negative (Kempers, 2011; NCCN, 2021; Rumilla, 2011).

Identification of Lynch syndrome is important for individuals with cancer because of the increased risk for metachronous Lynch syndrome cancers, and for their relatives because of autosomal dominant inheritance and potentially high penetrance. Once Lynch syndrome has been identified, surveillance provides an opportunity for early detection and possibly the prevention of cancer among mutation carriers.  

Two phenotypic tests performed on colon cancer tissue to identify individuals at risk for Lynch Syndrome are used by themselves or together as initial screening tests. These are used to screen individuals with colon cancer who have a clinical or family history suggesting Lynch Syndrome. The most widely used is a test which measures “microsatellite instability” or MSI. Microsatellites are repeated sequences of DNA which normally occur thousands of times across the genome. These sequences are made of repeating units of 1-6 base pairs in length. Each individual has microsatellites of a set length. MSI resulting from impaired DNA MMR occurs in 80%-90% of Lynch syndrome CRC tumors. MSI is a phenotypic expression of MMR gene mutations. The function of the MMR gene is to correct errors which spontaneously occur during DNA replication. The MMR gene products form a complex that binds to the mismatch, identifies the correct strand of DNA, then excises the error and repairs the mismatch. Cells carrying an MMR mutation can accumulate microsatellite replication errors resulting in novel repeated DNA sequences (microsatellites) or microsatellite instability. Five markers have been recommended by the National Cancer Institute to screen for MSI in HNPCC (Bethesda markers). MSI detection in two of these markers is considered a positive result or “high probability of MSI” (Sinn, 2009).

The second screening test for Lynch syndrome performed on colon cancer tissue involves IHC. IHC involves staining of tumor tissue for protein expression of the four mismatch genes associated with Lynch Syndrome (MLH1, MSH2, MSH6, and PMS2). If at least one of these four gene products is absent by IHC, the test is considered abnormal. Both MSI and IHC have a 5-15% false negative rate and are often used as preliminary screening tests to select individuals for gene mutation testing. MSI testing performance depends on the specific MMR mutation. For MLH1or MSH2 mutations, MSI has a sensitivity of 80-91% and specificity of 90% while for MSH6 or PMS2 the sensitivity is lower (55-77%) and the specificity is 90%. IHC testing, regardless of MMR gene mutation, has a sensitivity of 83% and specificity of 89% (EGAPP Working Group, 2009; NCCN, 2022).

Several criteria sets have been developed over the years to identify individuals who should be tested for possible Lynch Syndrome. The Amsterdam I criteria were proposed to identify individuals who were likely Lynch syndrome mutation carriers. These criteria require the presence of early onset CRC in addition to a family history which includes 3 CRCs involving two successive generations. The Amsterdam I criteria were later modified to include other Lynch syndrome-related malignancies. Based on the Amsterdam II criteria, Lynch syndrome should be suspected in individuals with 3 or more relatives with an HNPCC-related cancer in addition to all of the following:

• One of the affected individuals should be a first-degree relative of the other two;
• At least 2 successive generations should be affected;
• At least 1 of the relatives with cancer associated with HNPCC should be diagnosed prior to 50 years of age; and
• Familial adenomatous polyposis (FAP) should be excluded in any cases of colorectal cancer.

Although the Amsterdam II criteria are considered by many to be very stringent, it has been estimated that these criteria may miss as many as 68% of individuals with Lynch syndrome. It has also been estimated that approximately 50% of the families fulfilling the Amsterdam II criteria have an MMR gene mutation.

The National Cancer Institute developed the “Revised Bethesda Guidelines” in 2004 to identify those individuals with colon cancer whose tumors should be tested for MSI. These guidelines are now used to identify tumors that should be tested for mismatch repair defect, either by MSI and/or IHC. These guidelines are more sensitive than another criteria set, “Revised Amsterdam Minimum Criteria for Clinical Definition of HNPCC” or Amsterdam Criteria II. However, up to 50% of individuals with Lynch Syndrome fail to meet the revised Bethesda guidelines. Hampel and colleagues (2008) found that limiting colon tumor analysis only to those individuals who fulfill Bethesda criteria would fail to identify 28% of cases of Lynch syndrome. Some have advocated IHC and/or MSI screening of all CRCs and endometrial cancers regardless of age at diagnosis or family history. This approach was endorsed for colon cancer by the EGAPP Working Group from the Center for Disease Control (EGAPP Working Group, 2009). A survey of US hospitals reported that routine tumor testing with HHC, MSI or both is currently performed at 71% of NCI cancer centers, 36% of American College of Surgeons accredited community hospital cancer programs, but only 15% of community hospitals. Given the small portion (2%-4%) of colorectal cancers associated with the Lynch Syndrome, there is varied opinion as to which colorectal tumors should be screened with MSI and/ or IHC (Hampel, 2008; NCCN, 2022; Palomaki, 2009).

Prediction Models

Several validated computer models are available to estimate the likelihood that an individual affected with cancer carries a pathogenic variant in an MMR gene associated with Lynch syndrome. These include but are not limited to the MMRpro, MMRpredict, and PREMM1, 2, 5, 6 (Prediction of Mismatch Repair Gene Mutations in MLH1, MSH2, and MSH6) prediction models. While the general purpose of each model is the same, each has been developed differently.

• The MMRpro model incorporates personal and family history of CRC and endometrial cancer, age at diagnosis (or current age in unaffected family members) and the results of molecular tumor testing including MSI and IHC testing to determine the probability of a person having a deleterious germline mutation in the MLH1, MSH2, or MSH6 genes. The model also provides an estimate of future cancer risk in unaffected persons, including mutation carriers, those in whom no mutation is found and untested persons. It takes into consideration CRC, endometrial cancer, and MSI status, but it does not include any other Lynch syndrome associated cancers.
• The MMRPredict model includes sex, age at diagnosis of CRC, location of the tumor (distal vs proximal), multiple (synchronous or metachronous) CRCs, occurrence of endometrial cancer in any first-degree relatives and age at diagnosis of CRC in first-degree relatives to calculate the risk of an individual carrying a mutation in MLH1, MSH2 or MSH6 genes. This model does not specify gene-specific risk estimates.
• The PREMM1, 2, 5, 6 model provides an estimate of the risk of an MMR mutation and the probability of identifying a mutation in the MLH1, MSH2, and MSH6 genes based on personal and family history attributes (genotype-phenotype data). This does not address molecular tumor data in risk prediction or data on unaffected family members.

The NCCN (2022) recommends that testing for Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM sequence analysis) includes individuals who meet the Bethesda guidelines or the Amsterdam II criteria, who have a CRC 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.

Familial Adenomatous Polyposis (FAP) and Attenuated FAP

Classical FAP and attenuated FAP (AFAP) are autosomal dominant genetic disorders caused by a germline mutation in the APC (adenomatous polyposis coli) gene. Nearly 80% of individuals with FAP have a truncating mutation of the APC gene. FAP accounts for less than 1% of all colorectal cancers, but individuals harboring APC gene mutations are recommended early enhanced screening, with colectomy or proctocolectomy when the polyp burden becomes heavy and cannot be effectively managed by polypectomy. A clinical diagnosis of classical FAP is based on the presence of at least 100 polyps although fewer polyps may be present in younger age groups. The lifetime risk for colon cancer (most are left sided) with classic FAP approaches 100% by the age 50. At older ages, individuals with FAP may exhibit hundreds to thousands of colonic adenomatous polyps. Individuals with FAP are also at a higher risk for developing other cancers, including duodenal cancer, hepatoblastoma and thyroid cancer. Other possible associated findings of individuals with FAP include desmoid tumors, and congenital hypertrophy of retinal pigment epithelium. Currently, family members are often diagnosed at adolescence with genetic testing for their specific familial mutation (NCCN, 2022).

Attenuated FAP is a variant of FAP with a later onset of disease and fewer adenomatous polyps, usually 10 to less than 100. Adenomatous polyps in AFAP are more likely to occur in the right colon and may take the form of diminutive sessile adenomatous polyps. The onset of colon cancer is later with AFAP, but by age 80 the risk of colon cancer is nearly 70%. Both FAP and AFAP have an increased risk of other cancers, including duodenal cancer, hepatoblastoma and thyroid cancer. Individuals with FAP and AFAP are also at increased risk of developing desmoid tumors which are nonmalignant, but may become life threatening due to their locally invasive and aggressive growth. Confirmation of FAP and AFAP requires the identification of a germline mutation in the APC gene (NCCN, 2022).

MYH-associated Polyposis (MAP)

MAP is an autosomal recessive inherited polyposis syndrome that predisposes some individuals to attenuated adenomatous polyposis and colorectal cancer. Mutations in the MutY human homolog (MUTYH or MYH) gene prevent cells from correcting mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The gene product is a DNA glycosylase which enables oxidative DNA damage repair. The majority of individuals with MAP generally have fewer than 100 polyps although there are some instances where the individuals have greater than 1000 polyps. Traditional serrated adenomas as well as hyperplastic polyps and sessile serrated polyps (SSP) may also be seen in this setting. Some individuals with MAP may also meet the criteria for serrated polyposis syndrome (SPS). The median age of affected individuals at the time of diagnosis is typically between the mid-40s and the late 50s. Individuals with MAP develop fewer adenomas at a later age than individuals with APC mutations, but also carry a high risk of CRC (35-63%). Studies of multiple FAP registries have shown that 7%-19% of individuals with the FAP phenotype but without detectable APC mutation carry biallelic mutations in the MYH gene (NCI, 2017).

Genetic testing for APC and/or MUTYH is important to distinguish between FAP/AFAP, MAP and colonic polyposis of unknown etiology. Grover and colleagues (2012) conducted a cross-sectional study of more than 7000 individuals and found that the prevalence of pathogenic APC mutation was 80% for individuals with at least 1000 adenomas, 56% for individuals with 100-999 adenomas, 10% for individuals with 20-99 adenomas, and 5% for those with 10-19 adenomas. In the same cohort, the prevalence of biallelic MUTYH mutations was 2%, 7%, 5% and 4%, respectively.

Genetic Counseling

According to the National Society of Genetic Counselors (NSGC, 2006), genetic counseling is the process of assisting individuals to understand and adapt to the medical, psychological and familial ramifications of a genetic disease. This process typically includes the guidance of a specially trained professional who:

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

Desmoid tumor: A type of benign, locally invasive fibrous tumor capable of growing anywhere in the body.

Familial adenomatous polyposis (FAP): An inherited disorder characterized by the presence of adenomatous polyps throughout the colon that commonly progress to develop colon cancer.

First-degree relative: Any relative who is a parent, sibling, or offspring.
The National Human Genome Research Institute of the National Institutes of Health (NIH) defines the following terms in the context of potential transmission of inherited conditions associated with genetic mutations as follows:

• First-degree relative: Any relative who shares approximately 50% of an individual’s genetic material, such as an individual’s parent (father or mother), full sibling (brother or sister), or offspring.
• Second-degree relative: Any relative who shares approximately 25% of an individual’s genetic material, such as an individual’s grandparent, grandchild, uncle, aunt, niece, nephew, or half-sibling.
• Third-degree relative: Any relative who shares approximately 12.5% of an individual’s genetic material, such as an individual’s first cousin, great grandparent, great grandchild, great uncle, great aunt, half-uncle, half-aunt, half-niece, or half-nephew.

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.

Hereditary nonpolyposis colorectal cancer (HNPCC [Lynch Syndrome]): An inherited colorectal cancer syndrome that accounts for 5% to 8% of all colorectal cancers.

Hypermethylation: A process that occurs when additional methyl groups are added to the cytosine or adenine DNA nucleotides.

Medullary thyroid cancer: The type of thyroid cancer that develops from the C cells of the thyroid gland.

Multiple endocrine neoplasia Type 2 (MEN2): A hereditary disorder in which individuals develop a type of thyroid cancer accompanied by recurring cancer of the adrenal glands.

Mutation: A change in DNA sequence.

Second-degree relative: Any relative who is a grandparent, grandchild, uncle, aunt, niece, nephew, or half-sibling.

Third-degree relative: Any relative who is a first cousin, great grandparent or great grandchild.

Peer Reviewed Publications:

1. Barnetson RA, Tenesa A, Farrington SM, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med. 2006; 354(26):2751-2763.
2. Dinh TA, Rosner BI, Atwood JC, et al. Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population. Cancer Prev Res. 2011; 4(1):9-22.
3. Goodfellow PJ, Billingsley CC, Lankes HA, et al. Combined microsatellite instability, MLH1 methylation analysis, and immunohistochemistry for Lynch syndrome screening in endometrial cancers from GOG210: An NRG oncology and gynecologic oncology group study. J Clin Oncol. 2015; 33(36):4301-4308.
4. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008; 26(35):5783-5788.
5. Kastrinos F, Balmaña J, Syngal S. Prediction models in Lynch syndrome. Fam Cancer. 2013; 12(2): 217-228.
6. Kastrinos F, Uno H, Ukaegbu C, et al. Development and validation of the PREMM5 model for comprehensive risk assessment of Lynch syndrome. J Clin Oncol. 2017; 35(19):2165-2172.
7. Kattentidt Mouravieva AA, Geurts-Giele IR, de Krijger RR, et al. Identification of familial adenomatous polyposis carriers among children with desmoid tumours. Eur J Cancer. 2012; 48(12):1867-1874.
8. Kempers MJ, Kuiper RP, Ockeloen CW, et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol. 2011; 12(1):49-55.
9. Kuiper RP, Vissers LE, Venkatachalam R, et al. Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Hum Mutat 2011; 32(4):407-414.
10. Niessen RC, Hofstra RM, Westers H, et al. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer. 2009: 48(8):737-744.
11. Palomaki GE, McClain MR, Melillo S, et al. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 2009; 11(1):42-65.
12. Ramsey SD, Clarke L, Etzioni R, et al. Cost-effectiveness of microsatellite instability screening as a method for detecting hereditary nonpolyposis colorectal cancer. Ann Intern Med. 2001; 135(8 Pt 1):577-588.
13. Resnick KE, Hampel H, Fishel R, Cohn DE. Current and emerging trends in Lynch syndrome identification in women with endometrial cancer. Gynecol Oncol. 2009; 114(1):128-134.
14. Resnick K, Straughn JM Jr, Backes F, et al. Lynch syndrome screening strategies among newly diagnosed endometrial cancer patients. Obstet Gynecol. 2009; 114(3):530-536.
15. Rumilla K, Schowalter KV, Lindor NM, et al. Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn. 2011; 13(1):93-99.
16. Sinn DH, Chang DK, Kim YH, et al. Effectiveness of each Bethesda marker in defining microsatellite instability when screening for Lynch syndrome. Hepatogastroenterology. 2009; 56(91-92):672-676.
17. Smith LD, Tesoriero AA, Wong EM, et al. Contribution of large genomic BRCA1 alterations to early-onset breast cancer selected for family history and tumour morphology: a report from The Breast Cancer Family Registry. Breast Cancer Res. 2011; 13(1):R14.
18. Strate LL, Syngal S. Hereditary colorectal cancer syndromes. Cancer Causes Control. 2005; 16(3):201-213.
19. Vasen HF. Clinical diagnosis and management of hereditary colorectal cancer syndromes. J Clin Oncol. 2000; 18(21 Suppl):81S-92S.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Gastroenterological Association. Medical position statement: hereditary colorectal cancer and genetic testing. Gastroenterology. 2001; 121:195-197.
2. Stjepanovic N, Moreira L, Carneiro F, et al. Hereditary gastrointestinal cancers: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019; 00:1-34.
3. Evaluation of Genomic applications in Practice and Prevention. Working Group: Genetic testing strategies of newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009; 11(1):35-41.
4. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc. 2014; 80(2):197-220.
5. Hegde M, Ferber M, Mao R, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014; 16(1):101-116.
6. National Cancer Institute. Genetics of Colorectal Cancer (PDQ) - Health Professional Version. Last updated April 12, 2022. Available at: https://www.cancer.gov/types/colorectal/hp/colorectal-genetics-pdq/. Accessed October 04, 2022.
7. 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. Accessed on October 06, 2022.
   • Genetic/Familial High-Risk Assessment: Colorectal. V1.2022. Revised June 08, 2022.
8. National Society of Genetic Counselors. Genetic Counselors' Scope of Practice. Available at: https://hpa.ucdavis.edu/sites/g/files/dgvnsk4121/files/docs/healthcareers_assets/geneticcounseling_assets/GC_Scope_of_prractice_final.pdf. Accessed on October 04, 2022.
9. National Society of Genetic Counselors' Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns. 2006; 5(2):77-83.
10. Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology position statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010; 28(5):893-901.
11. Stoffel EM, Mangu PB, Gruber SB, et al. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. 2015; 33(2):209-291.
12. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004; 96(4):261-268.
13. Vasen, HF, Watson P, Mecklin JP, et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999; 116(6):1453-1456.

1. National Library of Medicine (NLM). Genetics Home Reference. EPCAM. Reviewed April 2020. Available at: http://ghr.nlm.nih.gov/gene/EPCAM. Accessed October 04, 2022.

EPCAM
Attenuated Familial Adenomatous Polyposis (AFAP)
Familial Adenomatous Polyposis (FAP)
Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
Lynch Syndrome
MMRpredict
MMRpro
MYH-associated polyposis (MAP)
PREMM 1, 2, 6

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