Commercial

Medical Policy

Notification

Genetic Testing for Inherited Susceptibility to Colon Cancer and Microsatellite Instability Testing (Familial Adenomatous Polyposis and Lynch Syndrome) (AmeriHealth Administrators)

Notification Issued Date:

Title:

Genetic Testing for Inherited Susceptibility to Colon Cancer and Microsatellite Instability Testing (Familial Adenomatous Polyposis and Lynch Syndrome) (AmeriHealth Administrators)

Policy #:

06.02.10r

Policy

This policy only applies to members for whom AmeriHealth Administrators serves as the claims administrator and whose group has not enrolled in the UM vendor program. For those groups who have been given the option to enroll in the UM vendor program, this policy is no longer applicable upon their renewal effective date. Individual member benefits must be verified before/prior to providing services.

The intent of this policy is to communicate the coverage positions for genetic testing for inherited susceptibility to colon cancer and microsatellite instability testing. Although there are numerous forms of familial colon cancer syndromes, the intent of this policy is only to address familial adenomatous polyposis (FAP) and Lynch syndrome.

For information on policies related to this topic, refer to the Cross References section in this policy.

FAMILIAL ADENOMATOUS POLYPOSIS (FAP)/ADENOMATOUS POLYPOSIS COLI (APC) GENE MUTATIONS

MEDICALLY NECESSARY
Genetic testing for adenomatous polyposis coli (APC) gene mutations is considered medically necessary and, therefore, covered for either of the following:

At-risk relatives of individuals with FAP and/or a known APC mutation
Individuals with a differential diagnosis of attenuated FAP or MUTYH-associated polyposis (MAP) or Lynch syndrome
- Whether testing begins with APC mutations or screening for MMR mutations depends upon clinical presentation.

NOT MEDICALLY NECESSARY
Genetic testing for APC gene mutations of individuals with colorectal cancer who have a diagnosis of classical FAP is considered not medically necessary and, therefore, not covered, because the available published peer-reviewed literature does not support this use.

GENETIC TESTING FOR MUTYH GENE MUTATIONS

MEDICALLY NECESSARY
Genetic testing for MUTYH gene mutations is considered medically necessary and, therefore, covered when the following criterion is met:

Individuals with a differential diagnosis of attenuated FAP or MUTYH-associated polyposis (MAP) or Lynch syndrome and a negative result for APC gene mutations. Individuals without a family history (e.g., no parents or children with FAP) is consistent with MUTYH-associated polyposis (autosomal recessive).

GENETIC TESTING FOR MMR GENE (MLH1, MSH2, PMS2, and MSH6) MUTATIONS

MEDICALLY NECESSARY
Genetic testing for MMR gene mutations is considered medically necessary and, therefore, covered when any of the following criteria are met:

Individuals with colorectal cancer, to establish a diagnosis of Lynch syndrome.
Individuals with endometrial cancer and one first-degree relative diagnosed with a Lynch-associated cancer, for the diagnosis of Lynch syndrome.
At-risk relatives of individuals with Lynch syndrome with a known MMR mutation.
Individuals with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome. Whether testing begins with APC mutations or screening for MMR mutations depends upon clinical presentation.
Individuals without colorectal cancer but with a family history meeting the Amsterdam or revised Bethesda criteria, when no affected family members have been tested for MMR mutations.

GENETIC TESTING FOR EPCAM GENE MUTATIONS

MEDICALLY NECESSARY
Genetic testing for EPCAM gene mutations is considered medically necessary and, therefore, covered when any of the following criteria are met:

Individuals with colorectal cancer, for the diagnosis of Lynch syndrome when:
- Tumor tissue shows lack of MSH2 expression by immunohistochemistry and individual is negative for a germline mutation in MSH2; or
- Tumor tissue shows a high level of microsatellite instability and individual is negative for a germline mutation in MSH2, MLH1, PMS2, and MSH6; OR
At-risk relatives of individuals with Lynch syndrome with a known EPCAMmutation; OR
Individuals without colorectal cancer but with a family history meeting the Amsterdam or Revised Bethesda criteria, when no affected family members have been tested for MMR mutations, and when sequencing for MMR mutations is negative.

GENETIC TESTING FOR BRAF V600 OR MLH1 PROMOTER METHYLATION

Genetic testing for BRAF V600E or MLH1 promoter methylation is considered medically necessary and, therefore, covered to exclude a diagnosis of Lynch syndrome when MLH1 protein is not expressed in a colorectal cancer on immunohistochemical (IHC) analysis.

GENETIC COUNSELING

When a benefit exists, pre-test and post-test genetic counseling is considered medically necessary and, therefore, covered as an adjunct to the genetic testing.

EXPERIMENTAL/INVESTIGATIONAL

Genetic testing for all other gene mutations for Lynch syndrome or colorectal cancer is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

Simultaneous genetic testing (i.e., panel testing) for mutations in multiple genes for Lynch syndrome or colorectal cancer is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

NOT COVERED

Genetic testing of associated family members, without a Company benefit, is not eligible for reimbursement.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

Guidelines

When possible, initial genetic testing for FAP or Lynch syndrome should be performed in an affected family member so that testing in unaffected family members can focus on the mutation found in the affected family member.

For individuals with colorectal cancer being evaluated for Lynch syndrome, either the microsatellite (MSI) test, or the immunohistochemistry (IHC) test with or without the BRAF gene mutation test, should be used as an initial evaluation of tumor tissue prior to the MMR gene analysis. Both tests are not necessary. The IHC test may help direct which MMR gene likely contains a mutation, if any, and may provide additional information if the MMR genetic test is inconclusive.

At-risk refers to first-degree relatives defined as a blood relative with whom an individual shares approximately 50% of his/her genes, including the individual’s parents, full siblings, and children. Judgment should be used in the case of a small family pedigree, when extended family members may need to be included in the testing strategy.

AMSTERDAM II CRITERIA

Three or more relatives with a histologically verified HNPCC-associated cancer (colorectal, endometrial, ovarian, gastric, hepatobiliary, small bowel, pancreatic, or transitional cell cancer of the renal pelvis or ureter); and ALL of the following criteria should be present:

One is a first-degree relative of the other two relatives; AND
HNPCC-associated cancer involving at least two generations; AND
Cancer in one or more affected relatives diagnosed before 50 years of age; AND
Familial adenomatous polyposis excluded in any cases of colorectal cancer; AND
Tumors should be verified whenever possible.

BETHESDA CRITERIA

Individuals must meet ONE of the following criteria:

Individuals diagnosed with colorectal cancer before age 50; OR
Individuals with HNPCC-related cancer, including synchronous and metachronous colorectal cancers or associated extracolonic cancers regardless of age; OR
Individuals with colorectal cancer with the MSI-H histology diagnosed in a indiviual less than age 60; OR
Individuals with colorectal cancer and one or more first-degree relatives with colorectal cancer and/or HNPCC-related extracolonic cancer, if one of the cancers was diagnosed at age <50 years; OR
Individuals with colorectal cancer and colorectal cancer diagnosed in two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, genetic testing for colon cancer is covered under the medical benefits of the Company’s products when medical necessity criteria in the medical policy are met.

However, services that are identified in this policy as not medically necessary are not eligible for coverage or reimbursement by the Company.

Description

Colorectal cancer is one of the leading causes of cancer-related deaths among both men and women in the United States, accounting for approximately 10 percent of all cancer-related deaths. Familial adenomatous polyposis (FAP) and Lynch syndrome, formerly known as hereditary nonpolyposis colorectal cancer (HNPCC) are two types of hereditary colorectal cancer. Individuals in families with these inherited traits are at an increased risk for developing colorectal cancer. Approximately 5 percent to 10 percent of all colorectal cancers are caused by inherited genetic defects.

FAMILIAL ADENOMATOUS POLYPOSIS (FAP) AND ASSOCIATED VARIANTS

FAP is an autosomal-dominant inherited disease that is characterized by the presence of 20 or more (usually greater than 100) adenomatous polyps in the colon and rectum. The polyps usually appear during adolescence and, if left untreated, inevitably lead to colon cancer. Individuals with FAP may be advised to have a prophylactic colectomy once florid polyposis develops. It is estimated that FAP accounts for approximately 1 percent of colorectal cancer cases. It may also be associated with osteomas of the jaw, skull, and limbs; sebaceous cysts; and pigmented spots on the retina, commonly referred to as Gardner’s syndrome.

Genetic testing should be initiated if a family member has FAP. The genetic mutation that occurs in FAP is found in the adenomatous polyposis coli (APC) gene, located on chromosome 5. The APC mutation results in altered protein length in about 80 percent to 85 percent of FAP cases. If the individual tests positive for the APC mutation, then genetic testing may be offered to all at-risk relatives. At-risk family members include first-degree relatives of the proband (ie, parents, siblings, children). Intensive surveillance for at-risk family members who have not inherited this genetic mutation is unnecessary, as the risk to these individuals would be the same as that of the general population. The risk to siblings depends on the status of the parents. If neither parent is affected, the risk to the siblings would be equivalent to the risk to the general population. Children born to an individual with FAP have a 50 percent chance of inheriting the mutation.

An alteration in the APC gene termed I1307K has been found in people of Ashkenazi Jewish descent and appears to be associated with an increase in colorectal cancer risk. The APC I1307K mutation differs from other APC gene mutations in that the mutation itself does not cause colon cancer. Instead, an unstable spot is created on the gene that makes it more susceptible to additional genetic changes that may lead to colorectal cancer.

A subset of FAP individuals may have attenuated FAP (AFAP), which is identified by 10-99 accruing colorectal adenomas that occur later in life than classical FAP. Classical FAP is characterized by colorectal cancer occurring around the age of 50-55 years, having fewer extraintestinal cancers, with an overall higher risk of colorectal cancer of 70% by 80 years of age. Individuals with AFAP have a 30% or less risk of carrying the APC mutations. Some of these individuals will instead have mutations in the MUTYH (formerly MYH) gene and are then diagnosed with MUTYH-associated polyposis (MAP). MAP occurs with a frequency approximately equal to FAP, with some variability among prevalence estimates for both. While clinical features of MAP are similar to FAP or AFAP, a strong multigenerational family history of polyposis is absent. Biallelic MUTYH mutations are associated with a cumulative colorectal cancer risk of about 80% by age 70, whereas monoallelic MUTYH mutation-associated risk of colorectal cancer appears to be relatively minimal. Thus, inheritance for high-risk colorectal cancer predisposition is autosomal recessive, in contrast to FAP. When relatively few (i.e., between 10 and 99) adenomas are present and family history is unavailable, the differential diagnosis may include both MAP and Lynch syndrome; genetic testing in this situation could include APC, MUTYH if APC is negative for mutations, and screening for mutations associated with Lynch syndrome.

Genetic testing for APC mutations may be considered for the following types of individuals:

Family members of individuals with FAP and a known APC mutation. Those without the specific mutation have not inherited the susceptibility gene and can forego intense surveillance (although they retain the same risk as the general population and should continue an appropriate level of surveillance).
Individuals with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome. These individuals do not meet the clinical diagnostic criteria for classical FAP, and have few adenomatous colonic polyps.
Individuals with colon cancer with a clinical picture or family history consistent with classical FAP.

LYNCH SYNDROME

Individuals with Lynch syndrome, formerly known as hereditary nonpolyposis colorectal cancer (HNPCC), have a predisposition to colorectal cancer and other malignancies related to having an inherited mutation in a DNA mismatch repair (MMR) gene. Lynch syndrome refers to those with an existing cancer and those who have not yet developed cancer. The term, hereditary nonpolyposis colorectal cancer (HNPCC), was used before the discovery of the MMR mutations. Use of the term, Lynch syndrome, has been recommended in several recent publications.

Lynch syndrome is characterized by colorectal cancer diagnosed at a young age with tumors that usually develop in the right side of the colon. It is estimated to account for 2 to 4 percent of colorectal cancer cases.Lynch syndrome is also associated with an increased risk of endometrial, ovarian, urinary tract, and biliary tract cancer. Family history is often the key to identifying individuals with Lynch syndrome. The lifetime risk of individuals with Lynch syndrome developing colorectal cancer is about 40 percent by age 70.

The genetic mutation associated with Lynch syndrome occurs in one of several DNA MMR genes. These genes are known as MLH1, MSH2, PMS1, PMS2, and MSH6, and are located on chromosome 2, 3, or 7. The function of these genes is to repair DNA that is damaged during replication. Routine testing of the PMS1 gene is usually not performed because mutations of these genes occur in only about 6 percent of HNPCC-affected families. The MLH1 and MSH2 genes are most commonly mutated in individuals with Lynch syndrome. Mutations of these genes may result in alterations in the repeating sequences of bases, referred to as microsatellites. Microsatellites are repeated sequences of DNA. Each individual has microsatellites of a set length. If abnormally long or short microsatellites are noted in an individual's DNA, the condition is called microsatellite instability (MSI) or replication error (RER). MSI can be classified as high frequency (MSI-H), low frequency (MSI-L), or stable (MSS), depending on the percentage of microsatellites that exhibit instability. If tumor tissue is identified on biopsy, MSI analysis is performed on the tumor tissue, which is then compared with the individual's unaffected tissue. If MSI is detected in the tumor cells, it may indicate a mutated DNA MMR repair gene. However, the presence of MSI-H does not confirm a diagnosis of Lynch syndrome. Although MSI-H is found in approximately 95 percent of Lynch syndrome cancers, it is also found in approximately 10 percent to 15 percent of sporadic colorectal cancers with no evidence of Lynch syndrome. Because MSI-H tumors are highly suggestive of Lynch syndrome, additional testing should be performed to identify possible mutations in the MMR genes (usually MLH1 and MSH2). For individuals with MSI-L or MSS tumors, further testing is unlikely to yield any information on mutations in the MMR genes.

MSI-H tumors can be further evaluated by immunohistochemistry (IHC) for the expression of MMR proteins hMLH1 and hMSH2. The absence or reduced expression of MMR proteins in tumor tissue may indicate the presence of a mutation or pinpoint the underlying mutated MMR gene. However, the possibility also exists for IHC assays to show loss of expression when, in fact, Lynch syndrome mutation testing is negative. These mutations may be in regulatory elements that cannot be detected. Because all families with Lynch syndrome do not have a germline mutation of hMLH1 or hMSH2, IHC testing is unlikely to replace MSI testing.

Novel deletions have been reported to affect the expression of the MSH2 MMR gene in the absence of an MSH2 gene mutation, and thereby cause Lynch syndrome. In these cases, deletions in EPCAM, the gene for the epithelial cell adhesion molecule, are responsible. EPCAM testing has been added to many Lynch syndrome profiles and is conducted only when tumor tissue screening results are MSI-high, and/or IHC shows a lack of MSH2 expression, but no MSH2 mutation is found by sequencing.

Guidelines have been developed in an attempt to identify which individuals with colorectal cancer should undergo genetic testing for Lynch syndrome mutations.

An individual must meet all of the Amsterdam II criteria in order to proceed with genetic testing for Lynch syndrome mutations. However, for individuals whose small family size prevents them from meeting these criteria, genetic testing for Lynch syndrome mutations may be provided when the following criterion is met: two first-degree relatives must have colorectal cancers involving at least two generations, with at least one individual diagnosed by 55 years of age.

The Bethesda guidelines were developed to help determine which individuals who have Lynch syndrome-- related cancers, but don't meet Amsterdam II criteria, should proceed to genetic testing. Because Lynch syndrome tumors are characterized by microsatellite instability (MSI), the Bethesda guidelines identify affected individuals who should undergo MSI analysis. MSI analysis should always be performed before proceeding with full mutation analysis of MLH1 and MSH2.

Genetic testing for Lynch syndrome may also be indicated in first-degree relatives of an affected family member who has tested positive for a mutation. A positive result may establish a basis for testing unaffected family members. A negative test for a gene mutation in an at-risk individual can then be reliably interpreted as a true negative, which would place the individual in the same risk category as the general population. Testing at-risk individuals without knowing the gene status of the family could result in a false-negative interpretation because not all mutations can be detected by current assays; additionally, mutations may be present in genes other than those being tested.

Recommendations for genetic testing for Lynch syndrome include:

Family members of individuals with Lynch syndrome with a known MMR mutation; family members would be tested only for the family mutation; those testing positive would benefit from early and increased surveillance to prevent future colorectal cancer.
Individuals with a differential diagnosis of Lynch syndrome vs. attenuated FAP vs. MUTYH-associated polyposis.
Individuals with Lynch syndrome. Genetic testing of the proband with colorectal cancer likely benefits the proband where Lynch syndrome is identified and appropriate surveillance for associated malignancies can be initiated and maintained, and benefits family members by identifying the family mutation. (A "proband" is the clinically affected individual through whom a family is found that can be used to study the genetics of a particular disorder).

PRACTICE GUIDELINES AND POSITION STATEMENTS

NATIONAL COMPREHENSIVE CANCER NETWORK (NCCN)
National Comprehensive Cancer Network (NCCN) guidelines for Genetic/Familial High-Risk Assessment: Colorectal recommend 2 approaches to Lynch syndrome mutation screening of either: (1) all newly diagnosed colorectal and endometrial cancers or (2) indiviuals with CRC thar are diagnosed before age 70 and those ages 70 and older when meeting Bethesda guidelines. Additionally, the CRC screening guidelines also recommend screening for Lynch syndrome for all endometrial cancer indiviuals younger than 50 years. These guidelines note IHC and sometimes MSI testing may be performed at some centers on all newly diagnosed colorectal and endometrial cancer indiviuals to determine need for genetic testing for Lynch syndrome mutations regardless of family history. The guidelines note “evidence has shown 3 deletions in the EPCAM gene, which lead to hypermethylation of the MSH2 promoter and subsequent MSH2 silencing, are an additional cause of Lynch syndrome.” Genetic testing is recommended for at-risk family members of indiviuals with positive mutations in MLH1, MSH2, MSH6, or PMS2. The NCCN guidelines also indicate BRAF V600E testing or MLH1 promoter methylation testing may be used when MLH1 is not expressed in the tumor on IHC analysis to exclude a diagnosis of Lynch syndrome. As noted in the NCCN guidelines, “the presence of a BRAF mutation indicates MLH1 expression is downregulated by somatic methylation of the promoter region of the gene and not by germline mutation.” These guidelines also address FAP (classical and attenuated), and MAP, consistent with the information in this policy.

NCCN guidelines for colon cancer recommend colon cancer indiviuals 70 years or younger and those older than 70 years of age that meet the Bethesda guidelines be tested for the MMR protein for possible Lynch syndrome. The colon cancer guidelines also indicate all colon cancer indiviuals should be questioned about family history and considered for risk assessment as per NCCN colorectal screening guidelines. NCCN guidelines on uterine neoplasms indicate all endometrial cancer indiviuals, especially those younger than 50 years, should be considered for testing for genetic mutations such as Lynch syndrome.

THE EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY (ESMO)
The European Society for Medical Oncology (ESMO) published clinical practice guidelines for familial CRC risk in 2010. These guidelines addressed Lynch syndrome, familial adenomatous polyposis, and MAP. No specific recommendations were made regarding how to initially identify Lynch syndrome cases; several methods, including clinical criteria and universal screening of all CRC cases, were mentioned. Other ESMO recommendations are consistent with the current state of evidence as described in this description section of the policy document.

AMERICAN SOCIETY OF CLINICAL ONCOLOGY AND SOCIETY OF SURGICAL ONCOLOGY
The American Society of Clinical Oncology and the Society of Surgical Oncology recommends offering prophylactic total abdominal hysterectomy to females with CRC who have completed childbearing or to women undergoing abdominal surgery for other conditions, especially when there is a family history of endometrial cancer. This recommendation is based on the high rate of endometrial cancer in mutation-positive individuals and the lack of efficacy of screening.

SUMMARY

Results of testing for the adenomatous polyposis coli (APC) mutation in individuals with a family history of familial adenomatous polyposis (FAP), or a known APC mutation in the family, lead to changes in surveillance and prophylactic treatment. For indiviuals with a positive result, enhanced surveillance and/or prophylactic treatment will reduce the future incidence of colon cancer and improve health outcomes. A related familial polyposis syndrome, MUTYH-associated polyposis (MAP) syndrome, is associated with mutations in the MUTYH gene. Testing for this genetic mutation may have clinical value when the differential diagnosis includes both FAP and MAP, because distinguishing between the two leads to different management strategies. In some cases, Lynch syndrome may be part of the same differential diagnosis, depending on presentation.

A substantial portion of indiviuals with colorectal cancer (CRC) will be found to have Lynch syndrome, which is associated with mutations in the mismatch repair (MMR) gene. A positive genetic test for the MMR mutation can lead to enhanced surveillance, changes in recommendations about treatment options, and possible prophylactic treatment for other Lynch syndrome malignancies. Therefore, testing for Lynch syndrome in indiviuals with newly diagnosed CRC and in indiviuals at high risk for Lynch syndrome, defined by meeting the clinical criteria such as Amsterdam II or Revised Bethesda, may have clinical value. Additionally, immunohistochemical testing for BRAF V600E or MLH1 promoter methylation may have clinical value to exclude a diagnosis of Lynch syndrome when MLH1 is not expressed in the colorectal tumor.

Women with endometrial cancer are also at risk for Lynch syndrome, at a low prevalence; the prevalence is increased substantially when the population is limited to those (at any age) with a first-degree relative diagnosed with a Lynch-associated cancer. Those found to have a MMR mutation will also benefit from enhanced CRC surveillance and prophylactic treatments. Therefore, testing for Lynch syndrome in indiviuals with newly diagnosed endometrial cancer who also have a first-degree relative diagnosed with a Lynch-associated cancer may have clinical value. The EPCAM mutation is less common than MMR mutations as a cause of Lynch syndrome and should be part of the diagnostic testing for Lynch syndrome in indiviuals who are negative for all MMR mutations but who screen positive for microsatellite instability (MSI) and lack MSH2 IHC evidence of protein expression.

References

Auranen A, Joutsiniemi T. A systematic review of gynecological cancer surveillance in women belonging to hereditary nonpolyposis colorectal cancer (Lynch syndrome) families. Acta Obstet Gynecol Scand. 2011;90(5):437-444.

Avezzu A, Agostini M, Pucciarelli S, et al. The role of MYH gene in genetic predisposition to colorectal cancer: another piece of the puzzle. Cancer Lett. 2008;268(2):308-313.

Balaguer F, Castellvi-Bel S, Castells A, et al. Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study. Clin Gastroenterol Hepatol. 2007;5(3):379-387.

Balmana J, Castells A, Cervantes A. Familial colorectal cancer risk: ESMO Clinical Practice Guidelines. Ann Oncol. 2010;21 Suppl 5:v78-81.

Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Genetic Testing for Inherited Susceptibility to Colorectal Cancer: Part I – Adenomatous Polyposis Coli Gene Mutations. TEC Assessments 1998; Volume 13, Tab 10.

Boland CR, Shike M. Report from the Jerusalem workshop on Lynch syndrome-hereditary nonpolyposis colorectal cancer. Gastroenterology. 2010;138(7):2197 e2191-2197.

Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305(22):2304-2310.

Bonis P, Trikalinos T, Chung M. Hereditary Nonpolyposis Colorectal Cancer: Diagnostic Strategies and Their Implications. Evidence Report/Technology Assessment No. 150 (Prepared by Tufts-New England Medical Center Evidence-based Practice Center under Contract No. 290-02-0022). 2007;AHRQ Publication No. 07- E008.(May). http://www.ncbi.nlm.nih.gov/books/NBK38285/. Accessed October 27, 2014.

Bouzourene H, Hutter P, Losi L, et al. Selection of indiviuals with germline MLH1 mutated Lynch syndrome by determination of MLH1 methylation and BRAF mutation. Fam Cancer. 2010;9(2):167-172.

Burke W, Petersen G, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA. 1997;277(11):915-919.

Burt RW, Jasperson KW. APC-associated polyposis conditions. 2008;
http://www.ncbi.nlm.nih.gov/pubmed/20301519. Accessed October 27, 2014.

Canard G, Lefevre JH, Colas C, et al. Screening for Lynch Syndrome in Colorectal Cancer: Are We Doing Enough? Ann Surg Oncol. 2011.

Capper D, Voigt A, Bozukova G, et al. BRAF V600E-specific immunohistochemistry for the exclusion of Lynch syndrome in MSI-H colorectal cancer. Int J Cancer. 2013;133(7):1624-1630.

Clarke BA, Cooper K. Identifying Lynch syndrome in individuals with endometrial carcinoma: shortcomings of morphologic and clinical schemas. Adv Anat Pathol. 2012;19(4):231-238.

de Vos tot Nederveen Cappel WH, Nagengast FM, Griffioen G, et al. Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on 114 families. Dis Colon Rectum. 2002;45(12):1588-1594.

de Vos tot Nederveen Cappel WH, Buskens E, van Duijvendijk P, et al. Decision analysis in the surgical treatment of colorectal cancer due to a mismatch repair gene defect. Gut. Dec 2003;52(12):1752-1755. PMID 14633956.

Durno CA, Holter S, Sherman PM, et al. The gastrointestinal phenotype of germline biallelic mismatch repair gene mutations. Am J Gastroenterol. 2010;105(11):2449-2456.

Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009;11(1):35-41.

Fitzgibbons RJ, Jr., Lynch HT, Stanislav GV, et al. Recognition and treatment of indiviuals with hereditary nonpolyposis colon cancer (Lynch syndromes I and II). Ann Surg. 1987;206(3):289-295.

Gala M, Chung DC. Hereditary colon cancer syndromes. Semin Oncol. 2011;38(4):490-499.

Goel A, Nagasaka T, Spiegel J, et al. Low frequency of Lynch syndrome among young indiviuals with non-familial colorectal cancer. Clin Gastroenterol Hepatol. 2010;8(11):966-971.

Goodfellow PJ, Buttin BM, Herzog TJ, et al. Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci U S A. 2003;100(10):5908-5913.

Grandval P, Baert-Desurmont S, Bonnet F, et al. Colon-specific phenotype in Lynch syndrome associated with EPCAM deletion. Clin Genet. 2012;82(1):97-99.

Guillem JG, Wood WC, Moley JF, et al. ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol. 2006;24(28):4642-4660.

Hampel H, Frankel W, Panescu J, et al. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer indiviuals. Cancer Res.2006;66(15):7810-7817.

Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among indiviuals with colorectal cancer. J Clin Oncol. 2008;26(35):5783-5788.

Hesson LB, Hitchins MP, Ward RL. Epimutations and cancer predisposition: importance and mechanisms. Curr Opin Genet Dev. 2010;20(3):290-298.

Hitchins MP. Inheritance of epigenetic aberrations (constitutional epimutations) in cancer susceptibility. Adv Genet. 2010;70:201-243.

Jin M, Hampel H, Zhou X, et al. BRAF V600E mutation analysis simplifies the testing algorithm for Lynch syndrome. Am J Clin Pathol. 2013;140(2):177-183.

Kastrinos F, Syngal S. Recently identified colon cancer predispositions: MYH and MSH6 mutations. Semin Oncol. 2007;34(5):418-424.

Kastrinos F, Syngal S. Screening indiviuals with colorectal cancer for Lynch syndrome: what are we waiting for? J Clin Oncol. 2012;30(10):1024-1027.

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.

Kloor M, Voigt AY, Schackert HK, et al. Analysis of EPCAM protein expression in diagnostics of Lynch syndrome. J Clin Oncol. 2011;29(2):223-227.

Kovacs ME, Papp J, Szentirmay Z, et al. Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat. 2009;30(2):197-203.

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.

Kwon JS, Scott JL, Gilks CB, et al. Testing women with endometrial cancer to detect Lynch syndrome. J Clin Oncol. 2011;29(16):2247-2252.

Leenen CH, van Lier MG, van Doorn HC, et al. Prospective evaluation of molecular screening for Lynch syndrome in indiviuals with endometrial cancer </= 70 years. Gynecol Oncol. 2012;125(2):414-420.

Lefevre JH, Parc Y, Svrcek M, et al. APC, MYH, and the correlation genotype-phenotype in colorectal polyposis. Ann Surg Oncol. 2009;16(4):871-877.

Ligtenberg MJ, Kuiper RP, Chan TL, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet. 2009;41(1):112-117.

Lipton LR, Johnson V, Cummings C, et al. Refining the Amsterdam Criteria and Bethesda Guidelines: testing algorithms for the prediction of mismatch repair mutation status in the familial cancer clinic. J Clin Oncol. 2004;22(24):4934-4943.

Lynch HT, Riegert-Johnson DL, Snyder C, et al. Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion. Am J Gastroenterol. 2011;106(10):1829-1836.

Masuda K, Banno K, Hirasawa A, et al. Relationship of lower uterine segment cancer with Lynch syndrome: A novel case with an hMLH1 germline mutation. Oncol Rep. 2012;28(5):1537-1543.

Moreira L, Balaguer F, Lindor N, et al. Identification of Lynch syndrome among indiviuals with colorectal cancer. JAMA. 2012;308(15):1555-1565.

National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Colon Cancer, v 2.2015. http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed October 27, 2014.

National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Colorectal Cancer Screening, v 1.2014. http://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf. Accessed
October 26, 2014.

National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Colorectal. v 2.2014.
http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Accessed October 26, 2014.

National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Uterine Neoplasms, v 1.2015. http://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed October 27, 2014.

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.

Obermair A, Youlden DR, Young JP, et al. Risk of endometrial cancer for women diagnosed with HNPCC-related colorectal carcinoma. Int J Cancer. 2010;127(11):2678-2684.

Overbeek LI, Ligtenberg MJ, Willems RW, et al. Interpretation of immunohistochemistry for mismatch repair proteins is only reliable in a specialized setting. Am J Surg Pathol. 2008;32(8):1246-1251.

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.

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.

Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med. 2006;354(3):261-269.

Schofield L, Watson N, Grieu F, et al. Population-based detection of Lynch syndrome in young colorectal cancer indiviuals using microsatellite instability as the initial test. Int J Cancer. 2009;124(5):1097-1102.

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.

Van Dalen R, Church J, McGannon E, et al. Patterns of surgery in indiviuals belonging to amsterdam-positive families. Dis Colon Rectum. 2003;46(5):617-620.

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.

Vogt S, Jones N, Christian D, et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. 2009;137(6):1976-1985 e1971-1910.

Wu Y, Berends MJ, Mensink RG, et al. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet. 1999;65(5):1291-1298.

Coding

CPT Procedure Code Number(s)

MEDICALLY NECESSARY

THE FOLLOWING CODES ARE USED TO REPRESENT APC TESTING
81201, 81202, 81203, 81301

THE FOLLOWING CODE IS USED TO REPRESENT BRAF TESTING
81210

THE FOLLOWING CODE IS USED TO REPRESENT EPCAM TESTING, (KNOWN FAMILIAL VARIANTS)
81403

THE FOLLOWING CODE IS USED TO REPRESENT MUTYH TESTING, (COMMON VARIANTS)
81401

THE FOLLOWING CODE IS USED TO REPRESENT MUTYH TESTING, (KNOWN FAMILIAL VARIANTS)
81406

THE FOLLOWING CODE IS USED TO MLH1 PROMOTER METHYLATION TESTING
81288

THE FOLLOWING CODES ARE USED TO REPRESENT MISMATCH REPAIR (MMR) GENE (MLH1, MSH2, PMS2 AND MSH6) TESTING
0238U, 81292, 81293, 81294, 81295, 81296, 81297, 81317, 81318, 81319, 81298, 81299, 81300

THE FOLLOWING CODE IS APPROPRIATE WHEN REPORTED BY A GENETIC COUNSELOR. WHEN PERFORMED BY A PHYSICIAN OR OTHER QUALIFIED HEALTH CARE PROFESSIONAL, THE PHYSICIAN OR OTHER QUALIFIED HEALTH CARE PROFESSIONAL SHOULD USE THE APPROPRIATE EVALUATION AND MANAGEMENT EXAM CODES
96040

EXPERIMENTAL/INVESTIGATIONAL
81435, 81436

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

C18.0 Malignant neoplasm of cecum

C18.2 Malignant neoplasm of ascending colon

C18.3 Malignant neoplasm of hepatic flexure

C18.4 Malignant neoplasm of transverse colon

C18.5 Malignant neoplasm of splenic flexure

C18.6 Malignant neoplasm of descending colon

C18.7 Malignant neoplasm of sigmoid colon

C18.8 Malignant neoplasm of overlapping sites of colon

C18.9 Malignant neoplasm of colon, unspecified

C19.0 Malignant neoplasm of rectosigmoid junction

C20.0 Malignant neoplasm of rectum

C21.0 Malignant neoplasm of anus, unspecified

C21.1 Malignant neoplasm of anal canal

C21.2 Malignant neoplasm of cloacogenic zone

C21.8 Malignant neoplasm of overlapping sites of rectum, anus and anal canal

D01.0 Carcinoma in situ of colon

D01.1 Carcinoma in situ of rectosigmoid junction

D01.2 Carcinoma in situ of rectum

D12.0 Benign neoplasm of cecum

D12.2 Benign neoplasm of ascending colon

D12.3 Benign neoplasm of transverse colon

D12.4 Benign neoplasm of descending colon

D12.5 Benign neoplasm of sigmoid colon

D12.6 Benign neoplasm of colon, unspecified

D12.7 Benign neoplasm of rectosigmoid junction

D12.8 Benign neoplasm of rectum

K62.1 Rectal polyp

K63.5 Polyp of colon

Z13.71 Encounter for nonprocreative screening for genetic disease carrier status

Z13.79 Encounter for other screening for genetic and chromosomal anomalies

Z15.09 Genetic susceptibility to other malignant neoplasm

Z31.5 Encounter for procreative genetic counseling

Z80.0 Family history of malignant neoplasm of digestive organs

Z85.030 Personal history of malignant carcinoid tumor of large intestine

Z85.038 Personal history of other malignant neoplasm of large intestine

Z85.040 Personal history of malignant carcinoid tumor of rectum

Z85.048 Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus

Z83.71 Family history of colonic polyps

Z71.83 Encounter for nonprocreative genetic counseling

Z86.010: Personal history of colonic polyps

HCPCS Level II Code Number(s)

THE FOLLOWING CODE IS USED TO REPRESENT INTERPRETATION AND REPORT

G0452 Molecular pathology procedure; physician interpretation and report

THE FOLLOWING CODE IS APPROPRIATE WHEN REPORTED BY A GENETIC COUNSELOR. WHEN PERFORMED BY A PHYSICIAN OR OTHER QUALIFIED HEALTH CARE PROFESSIONAL, THE PHYSICIAN OR OTHER QUALIFIED HEALTH CARE PROFESSIONAL SHOULD USE THE APPROPRIATE EVALUATION AND MANAGEMENT EXAM CODES

S0265 Genetic counseling, under physician supervision, each 15 minutes

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From 06.02.10r:

08/09/2023	This policy has been reissued in accordance with the Company's annual review process.
07/01/2022	This policy has been reissued in accordance with the Company's annual review process. The following disclaimer language…: This policy only applies to members for whom AmeriHealth Administrators serves as the claims administrator and whose group has not enrolled in the UM vendor program. For those groups who have been given the option to enroll in the UM vendor program, this policy is no longer applicable upon their renewal effective date. Individual member benefits must be verified before/prior to providing services. … is replacing this disclaimer language…: This policy only applies to members for whom AmeriHealth Administrators serves as the claims administrator. For all other Independence members, refer to the policy entitled eviCore Lab Management Program.
06/01/2022	This policy has been reissued in accordance with the Company's annual review process.
03/24/2021	This policy has been reissued in accordance with the Company's annual review process.
01/02/2021	This version of the policy went through a code update process effective 01/01/2021, and procedure code 0238U was added to the policy.

Revisions From 06.02.10q:

10/09/2019	This policy has been reissued in accordance with the Company's annual review process.
11/21/2018	This policy has been reissued in accordance with the Company's annual review process.

Effective 10/05/2017 this policy has been updated to the new policy template format.

Version Effective Date:

1/1/2021

Version Issued Date:

1/4/2021

Version Reissued Date:

8/9/2023