This document addresses genetic testing for individuals who are at higher than average risk for the development of cancer.  Conditions addressed in this document include, but are not limited to the following:

• BRCA1 and BRCA2 mutations;
• Hereditary Non-Polyposis Colorectal Cancer (HNPCC [Lynch Syndrome]);
• Familial Adenomatous Polyposis (FAP);
• Medullary Thyroid Cancer;
• Multiple Endocrine Neoplasia Type 2, (MEN2) and
• MYH-associated Polyposis (MAP).

Medically Necessary: 

1. Medically Necessary Criteria for Specific Conditions (A - E):
   
   Note: Genetic testing is appropriate only when offered in a setting with adequately trained health care professionals to provide appropriate pre- and post-test counseling.
   
   1. BRCA1 and BRCA2
      
      Genetic testing for a BRCA1 or BRCA2 mutation, associated with genetic counseling, is considered medically necessary when ANY of the following criteria are met:
      • Individuals with breast cancer who have 1 relative with breast cancer diagnosed at an early age (less than 45 years) ; OR
      • Individuals with breast cancer diagnosed at an early age (premenopausal); OR
      • Individuals with breast cancer with multiple primary cancers or bilateral disease; OR
      • Individuals who developed epithelial ovarian/ fallopian tube/ primary peritoneal cancer; OR
      • Men who developed breast cancer at any age; OR
      • Individuals with a personal history of breast cancer, and diagnosed age less than 60 years with a triple negative breast cancer; OR
      • Individuals with a personal history of breast cancer, and diagnosed age less than 50 years with a limited family history; OR
      • Individuals with a history of breast and/or ovarian cancer at any age with two or more close blood relatives with pancreatic cancer at any age; OR
      • Individuals with a history of pancreatic adenocarcinoma at any age with two or more close blood relatives with breast and/or ovarian and/or pancreatic cancer at any age; OR
      • Individuals who have 1 or more first or second-degree relatives who meet ANY of the above criteria; when that relative(s) is (are) not available for testing; OR
      • Individuals with breast cancer who have 2 or more first, second or third-degree relatives (related through a single lineage) with breast or epithelial ovarian/ fallopian tube/ primary peritoneal cancer; OR
      • Relatives of individuals with documented mutations in either the BRCA1 or BRCA2 gene; OR
      • Individuals with a family history of 3 or more first, second or third-degree relatives with breast or epithelial ovarian/ fallopian tube/ primary peritoneal cancer, at least 1 of which has breast cancer that develops at or before age 50 years; OR
      • Individuals with breast cancer who belong to a population at risk for specific mutations due to ethnic background (e.g., Ashkenazi Jewish, Icelandic, Swedish, Hungarian or Dutch descent).
        
   2. Hereditary Non-Polyposis Colorectal Cancer (HNPCC [Lynch Syndrome])
      
      Genetic testing to detect mutations in the HNPCC genes, associated with genetic counseling, is considered medically necessary when ANY of the following criteria are met:
      • Individuals with 2 or more HNPCC-related tumors, (colorectal, endometrial, biliary tract, pancreas, ureter or renal pelvis, ovarian, brain, gastric, or small intestinal cancers, or sebaceous gland adenomas or keratoacanthomas), including synchronous and metachronous tumors irrespective of age; OR
      • Individuals with colorectal cancer and a first-degree relative with colorectal cancer or HNPCC-related cancer or colorectal adenoma; one of the cancers diagnosed at age less than 50 years, and the adenoma diagnosed at age less than 40 years; OR
      • Individuals with colorectal cancer or endometrial cancer diagnosed at age less than 50 years; OR
      • Individuals with right-sided colorectal cancer with an undifferentiated pattern on histopathology diagnosed at age less than 45 years; OR
      • Individuals with signet ring cell type colorectal cancer diagnosed at age less than 45 years; OR
      • Individuals with adenomas diagnosed at age less than 40 years; OR
      • In individuals with a first or second-degree relative with a known HNPCC mutation (Lynch syndrome in family).
        
   3. Familial Adenomatous Polyposis (FAP)
      
      Genetic testing to detect mutations in the Familial Adenomatous Polyposis (FAP) genes, associated with genetic counseling, is considered medically necessary in individuals who meet ANY of the following criteria:
      • Individuals with greater than 20 adenomatous colonic polyps during their lifetime; OR
      • First-or second-degree relatives of individuals diagnosed with Familial Adenomatous Polyposis (FAP); OR
      • First or second-degree relatives of individuals with a known FAP gene mutation.
        
   4. MYH-associated Polyposis (MAP)
      
      Genetic testing for MYH-associated polyposis (MAP), associated with genetic counseling, is considered medically necessary when #1 OR #2 of the following criteria is met:
      
      1. Individuals with greater than 10 adenomatous colonic polyps; or greater than 15 cumulative adenomas in 10 years; AND
         • Who have a recessive inheritance (family history positive only for siblings); OR
         • Who have undergone testing for adenomatous polyposis coli (APC) with negative results.
      2. The asymptomatic siblings of individuals with known MYH-associated polyposis (MAP).
         
   5. Medullary Thyroid Cancer and Multiple Endocrine Neoplasia Type 2 (MEN2), RET testing
      
      Genetic testing for the RET proto-oncogene point mutations for the purposes of assessing multiple endocrine neoplasia type 2 (MEN2) or medullary thyroid cancer risk, associated with genetic counseling, is considered medically necessary in individuals who meet ANY of the following criteria: 
      • Among members of families with defined RET gene mutations; OR
      • Among members of families known to be affected by inherited medullary thyroid cancer but not previously evaluated for RET mutations; OR
      • In individuals with sporadic medullary thyroid cancer.
        
2. Genetic testing for susceptibility to malignant diseases not listed above is considered medically necessary when the following criteria are met:
   
   • The genetic disorder is associated with a potentially significant cancer or has a lethal natural history; AND
   • The risk of the significant cancer from the genetic disorder cannot be identified through biochemical or other testing, AND
   • A specific mutation, or set of mutations, has been established in the scientific literature to be reliably associated with the disease; AND
   • The results of the genetic test may impact the medical management of the individual; AND
   • The use of the genetic test in directing therapy decisions will likely result in an improvement in net health outcomes; AND
   • Testing is accompanied by genetic counseling.

Investigational and Not Medically Necessary:

Genetic testing for cancer susceptibility is considered investigational and not medically necessary in individuals not meeting any of the criteria in sections I and II above, including but not limited to the BRACAnalysis^® Rearrangement Test [BART].  

BRCA1 and BRCA2
Genetic testing of BRCA1 and BRCA2 genes may influence individual management in a variety of ways.  Individuals with a gene mutation may consider increased surveillance for breast cancer, or potentially consider a prophylactic mastectomy or oophorectomy.  The family members of an individual with a known mutation, who test negative for a mutation, can forego increased surveillance and/or consideration of prophylactic surgery.  Genetic testing of BRCA1 and BRCA2 genes has emerged as a widely accepted test, when accompanied by genetic counseling. 

The BRACAnalysis^® Rearrangement Test™ (BART) is a refinement of the BRCA genetic tests and is purported to detect rare, large rearrangements of deoxyribonucleic acid (DNA) in the BRCA 1 and BRCA 2 genes which were previously undetected by standard genetic testing.  The manufacturer (Myriad Genetic Laboratories) reports that BART testing will identify an additional approximate 3% of BRCA 1 and BRCA2 mutations in very high-risk families and is intended for use only in women at an exceptionally high risk for breast cancer who have previously tested negative for BRCA 1 and BRCA 2 sequence mutations.  

Walsh and colleagues (2006) reported on probands from 300 families in the United States with 4 or more cases of breast or ovarian cancer but who had tested negative (wild-type) with commercial genetic tests for BRCA1 and BRCA2 mutations.  These individuals were screened using additional multiple DNA -based and RNA-based methods to detect genetic mutations including genomic rearrangements in BRCA1 and BRCA2.  Of the 300 individuals participating in the study, 35 (12%) carried previously undetected genomic rearrangements of BRCA 1 or BRCA2.  Palma and colleagues (2008) evaluated 251 individuals with an estimated BRCA mutation of greater than or equal to 10% using the Myriad II model.  In the 136 non-Ashkenazi Jewish probands, 36 (26%) had BRCA point mutations and 8 (6%) had genomic rearrangements, (with 7 in BRCA1 and 1 in BRCA2).  Point mutations were identified in 47 of the 115 (40%) Jewish probands.  There were no genomic rearrangements identified in the group without mutations.  In the non-Ashkenazi Jewish probands, genomic rearrangements accounted for 18% of all identified BRCA mutations.  The estimated prevalence of a mutation using the Myriad II model was not predictive of the presence of a genomic rearrangement.  While these studies suggest that there is an association between individuals with a high risk factor for BRCA1 or BRCA2 rearrangements, however, with regards to clinical utility, there is a lack of evidence that making clinical decisions based on the results of large genomic rearrangements is comparable to that of BRCA1 or BRCA 2 testing or results in improved outcomes.  Additional research is needed to see if these results can be replicated in a larger population.

Hereditary Non-Polyposis Colon Cancer (HNPCC [Lynch Syndrome]), Familial Adenomatous Polyposis and MYH-associated Polyposis

Genetic testing for hereditary colon cancers may affect individual management in a variety of ways.  A positive test might prompt additional surveillance or consideration of a prophylactic colectomy.  Frequently, FAP is immediately present due to the profusion of polyps.  However, the presence of greater than 20 polyps is suggestive but not diagnostic of FAP.  When a positive genetic test is present, individuals may consider a prophylactic colectomy. 

MYH-associated polyposis (MAP) is an autosomal recessive form of FAP that predisposes some individuals to attenuated adenomatous polyposis and colorectal cancer.  Mutations in the MutY human homolog (MYH) gene prevent cells from correcting mistakes that are made when DNA is copied (DNA replication) in preparation for cell division.  The majority of individuals with MAP generally have fewer than 100 polyps (15 – 100).  The median age of affected individuals at the time of diagnosis is typically between the mid 40s and the late 50s. 

Medullary Thyroid Cancer and Multiple Endocrine Neoplasia
There is adequate data to show that genetic tests for point mutation in the RET gene can identify those with an inherited susceptibility for medullary thyroid cancer.  Test results affect individual management by prompting thyroidectomy or continued biochemical monitoring in affected individuals, and by prompting discontinuation of monitoring in individuals who test negative.

BRCA1 and BRCA2
Between 5% and 10% of women with breast cancer develop the disease due to the inheritance of a mutated copy of BRCA1 or BRCA2 genes.  Families suspected of having hereditary breast and/or ovarian cancer are characterized by cancer occurring in premenopause, in multiple generations, often bilaterally and in a pattern suggesting an autosomal dominant pattern of inheritance.  A positive test result indicates that a person has inherited a known BRCA1 or BRCA2 gene mutation, and has an increased risk of breast and/or ovarian cancer.  Mutations of BRCA1 and BRCA2 are present in 1-2% of individuals of Ashkenazi Jewish ancestry.

As mentioned above, the BRACAnalysis^® Rearrangement Test™ (BART) is a refinement of the BRCA genetic tests and is purported to detect rare, large rearrangements of deoxyribonucleic acid (DNA) in the BRCA1 and BRCA2 genes which were previously undetected by standard genetic testing.  BART testing is purported to identify additional BRCA1 and BRCA2 mutations in women at high risk for breast cancer who have previously tested negative for BRCA1 and BRCA2 sequence mutations.

Hereditary Non-Polyposis Colon Cancer (HNPCC [Lynch Syndrome]), Familial Adenomatous Polyposis and MYH-associated Polyposis
There are multiple well-defined types of hereditary colorectal cancer, three of the most common of which are familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) 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%.  Recently 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.

MYH-associated polyposis (MAP) is an autosomal recessive form of FAP that increases the individual's risk of developing attenuated adenomatous polyposis and colorectal cancer.  There may also be an increased risk of polyps in the duodenum, although the incidence of duodenal polyposis is reported less frequently than in FAP.  The magnitude of the risk of duodenal cancer has not yet been defined.  As in the case of FAP, some individuals with MYH mutations may require colectomy, but the procedure is usually done at a later age than those with FAP.

Medullary Thyroid Cancer and Multiple Endocrine Neoplasia
Medullary cancer of the thyroid and multiple endocrine neoplasia are unusual types of malignancy; three distinct but related familiar cancer syndromes together are responsible for approximately one fourth of the cases.

Ashkenazi Jewish: A term for people of eastern European Jewish heritage.

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 to another.

Genetic counseling: A process involving the guidance of a specially trained professional in the evaluation of family history, medical records, and genetic test results, in assessing the risk of genetic diseases, understanding the ramifications of diagnosis, and explanation of available treatment options.

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.

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 to another.

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

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.

BRCA, HNPCC and FAP testing:
When Services may be Medically Necessary, when criteria are met: 

RET testing:
When Services may be Medically Necessary, when criteria are met: 

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

When services are also Investigational and Not Medically Necessary: 

Other malignant diseases:

When Services may be Medically Necessary, when criteria are met:

When services are Investigational and Not Medically Necessary:
For genetic susceptibility testing for other malignancies when criteria are not met

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Gad S, Scheuner MT, Pages-Berhouet S, et al. Identification of a large rearrangement of the BRCA1 gene using colour bar code on combed DNA in an American breast/ovarian cancer family previously studied by direct sequencing. J Med Genet. 2001; 38(6):388-392.
2. Gertner ME, Kebebew E. Multiple endocrine neoplasia type 2. Curr Treat Options Oncol. 2004; 5(4):315-325.
3. Leboulleux S, Baudin E, Travagli JP, et al. Medullary thyroid carcinoma. Clin Endocrinol. 2004; 61(3): 299-310.
4. Palma MD, Domchjeck SM, Stopfer J et al. The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families Cancer Res. 2008; 68(17):7006-7014.
5. 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.
6. Plaza-Menacho I, Burzynski GM, de Groot JW, et al. Current concepts in RET-related genetics, signaling and therapeutics. Trends Genet. 2006; 22(11):627-636.
7. Smith RA, Cokkinides V, Brawley OW.  Cancer screening in the United States, 2009: A review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin. 2009; 59(1):27-41.
8. Strate LL, Syngal S. Hereditary colorectal cancer syndromes. Cancer Causes Control. 2005; 16(3):201-213.
9. Walsh T, Casadei S, Coats KH et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer JAMA 2006; 295(12):1379-1388.
10. Weinstein LB. Selected genetic disorders affecting Ashkenazi Jewish families. Fam Community Health. 2007; 30(1):50-62.
11. Weitzel JN, Lagos VI, Cullinane CA, et al. Limited family structure and BRCA gene mutation status in single cases of breast cancer. JAMA. 2007; 297(23):2587-2595.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American College of Medical Genetics Foundation. Genetic susceptibility to breast cancer and ovarian cancer: Assessment, Counseling and Testing Guidelines. 1999. Available at: http://www.health.state.ny.us/nysdoh/cancer/obcancer/contents.htm.  Accessed on April 19, 2011.
2. American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 103: Hereditary Breast and Ovarian Cancer Syndrome. Obstetrics & Gynecology 2009; 113(4):957-966.
3. American Gastroenterological Association. Medical position statement: Hereditary colorectal cancer and genetic testing. Gastroenterology. 2001; 121:195-197. Available at: http://www.med.upenn.edu/gastro/documents/AGApositionstatementhereditarycoloncancertesting.pdf.  Accessed on April 19, 2011.
4. National Comprehensive Cancer Network (NCCN).  Breast cancer screening and diagnosis. Clinical Practice Guidelines in Oncology. V.1.2011. For additional information visit the NCCN website at: http://www.nccn.org.  Accessed on April 19, 2011.
5. National Comprehensive Cancer Network (NCCN). Colorectal Cancer Screening. Clinical Practice Guidelines in Oncology. V.2.2011. For additional information visit the NCCN website at:  http://www.nccn.org. Accessed on April 19, 2011.
6. National Comprehensive Cancer Network (NCCN). Genetic/familial high-risk assessment: Breast and ovarian. Clinical Practice Guidelines in Oncology. V.1.2011. For additional information visit the NCCN website at: http://www.nccn.org. Accessed on April 19, 2011.
7. National Comprehensive Cancer Network (NCCN).  Thyroid Carcinoma Clinical Practice Guidelines in Oncology. V.1, 2011. For additional information visit the NCCN website at: http://www.nccn.org. Accessed on April 19, 2011.
8. National Library of Medicine (NLM). Genetics Home Reference. Available at: http://ghr.nlm.nih.gov/ghr/glossary/firstdegreerelative. and http://ghr.nlm.nih.gov/ghr/glossary/seconddegreerelative  Accessed on April 19, 2011.
9. 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. Available at: http://jco.ascopubs.org/content/28/5/893.full.pdf+html.  Accessed on April 19, 2011.
10. United States Preventive Services Task Force: Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility: Recommendation Statement: The Internet Journal of Oncology. 2006. Volume 4 Number 2. Available at: http://www.ispub.com/ostia/index.php?xmlFilePath=journals/ijo/vol3n1/brca.xml#documentHeading-Summaryof Recommendations.   Accessed on April 19, 2011.

BART (BRCA1/2 Rearrangement Test)
BRCA1
BRCA2
Familial Adenomatous Polyposis (FAP)
Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
Lynch Syndrome
Medullary Thyroid Cancer
Multiple Endocrine Neoplasia
MYH-associated polyposis (MAP)