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DESCRIPTIONGenetic testing is available for both affected individuals, as well as those at risk, for various types of hereditary cancer. This policy describes genetic testing for familial adenomatous polyposis (FAP), Lynch Syndrome (formerly known as hereditary nonpolyposis colorectal cancer or HNPCC), MYH-associated polyposis, and Lynch syndrome-related endometrial cancer.
There are currently 2 well-defined types of hereditary colorectal cancer, familial adenomatous polyposis (FAP) and Lynch syndrome (formerly, hereditary nonpolyposis colorectal cancer or HNPCC). Lynch syndrome has been implicated in some endometrial cancers as well.
Familial adenomatous polyposis and associated variants
Germline mutations in the adenomatous polyposis coli (APC) gene, located on chromosome 5, are responsible for FAP and are inherited in an autosomal dominant manner. Mutations in the APC gene result in altered protein length in about 80% to 85% of cases of FAP. A specific APC gene mutation (I1307K) has been found in subjects of Ashkenazi Jewish descent that may explain a portion of the familial colorectal cancer occurring in this population.
A subset of FAP patients may have attenuated FAP (AFAP), typically characterized by fewer than 100 cumulative colorectal adenomas occurring later in life than in classical FAP, colorectal cancer occurring at an average age of 50-55 years, but a high lifetime risk of colorectal cancer of about 70% by age 80 years. The risk of extraintestinal cancer is lower compared with classical FAP but still high at an estimated cumulative lifetime risk of 38% compared with the general population. Only 30% or fewer of AFAP patients have APC mutations; some of these patients instead have mutations in the MUTYH (formerly MYH) gene and are then diagnosed with MYH-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, although still under debate. 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.
It is important to distinguish among classical FAP, attenuated FAP, and MAP (mono- or biallelic) by genetic analysis because recommendations for patient surveillance and cancer prevention vary according to the syndrome.
Genetic testing for APC mutations may be considered for the following types of patients:
Lynch syndrome is estimated to account for 3% to 5% of colorectal cancer and is also associated with an increased risk of other cancers such as endometrial, ovarian, urinary tract, and biliary tract cancer. Lynch syndrome is associated with a risk of developing colorectal cancer by age 70 years of approximately 27% to 45% for men, and 22% to 38% for women, after correction for ascertainment bias. Lynch syndrome patients who have colorectal cancer also have an estimated 16% risk of a second primary within 10 years.
Lynch syndrome is associated with any of a large number of possible mutations in 1 of several MMR genes, known as MLH1, MSH2, MSH6, and PMS2 and rarely MLH3, PMS1, and EXO1. Risk of all Lynch syndrome-related cancers is markedly lower for carriers of a mutation in the MSH6 and PMS2 genes, although for most cancers still significantly higher than that of the general population. Estimated cumulative risks of any associated cancer for a carrier of a mutation in any MMR gene do not begin to increase until after age 30 years.
Lynch syndrome mutations are heterozygous; that is, only 1 of the 2 gene alleles contains a mutation. In rare cases both alleles contain the mutation, ie, biallelic MMR gene mutations. This unusual syndrome has been described in multiple families and is to a large extent the result of consanguinity. Children with biallelic MMR mutations may develop extracolonic cancers in childhood, such as brain tumors, leukemias, or lymphomas. Those unaffected or surviving early malignancies are at high risk of later CRC (average age of CRC diagnosis, 16.4 years). Family history may not suggest Lynch syndrome. Before cancer diagnosis, patients may have multiple adenomatous polyps and thus may have an initial differential diagnosis of attenuated FAP versus MUTYH-associated polyposis versus Lynch syndrome.
About 70% of Lynch syndrome patients have mutations in either MLH1 or MSH2. Testing for MMR gene mutations is often limited to MLH1 and MSH2 and, if negative, then MSH6 and PMS2 testing. Large gene sizes and the difficulty of detecting mutations in these genes make direct sequencing a time- and cost-consuming process. Thus, additional indirect screening methods are needed to determine which patients should proceed to direct sequencing for MMR gene mutations. Available screening methods are microsatellite instability (MSI) testing or immunohistochemical (IHC) testing. BRAF testing is an optional screening method that may be used in conjunction with IHC testing for MLH1 to improve efficiency. A methylation analysis of the MLH1 gene can largely substitute for BRAF testing, or be used in combination to slightly improve efficiency.
Mutations in MMR genes result in a failure of the mismatch repair system to repair errors that occur during the replication of DNA in tumor tissue. Such errors are characterized by the accumulation of alterations in the length of simple, repetitive microsatellite (2 to 5 base repeats) sequences that are distributed throughout the genome, termed MSI and resulting in an MSI-high tumor phenotype. MSI testing was standardized subsequent to a 2004 National Cancer Institute (NCI) workshop. Methodologic studies have also shown the importance of laser microdissection of the tumor tissue, comparison of tumor and normal cells, and a minimum proportion of tumor in relation to the quality of the test results. While the sensitivity of MSI testing is high, the specificity is low because approximately 10% of sporadic CRC are MSI-positive due to somatic hypermethylation of the MLH1 promoter. Additionally, some tumors positive for MSH6 mutations are associated with the MSI-low phenotype rather than MSI-high; thus MSI-low should not be a criterion against proceeding to MMR mutation testing.
Absent or reduced protein expression may be a consequence of an MMR gene mutation. IHC assays for the expression of MLH1, MSH2, MSH6, and PMS2 can be used to detect loss of expression of these genes and to focus sequencing efforts on a single gene. It is also possible for IHC assays to show loss of expression, and thus indicate the presence of a mutation, when sequencing is negative for a mutation. In such cases, mutations may be in unknown regulatory elements and cannot be detected by sequencing of the protein coding regions. Thus IHC may add additional information.
The BRAF gene is often mutated in colorectal cancer; when a particular BRAF mutation (V600E, a change from valine to glutamic acid at amino acid position 600 in the BRAF protein) is present, to date no MLH1 gene mutations have been reported. Therefore, patients negative for MLH1 protein expression by IHC, and therefore potentially positive for an MLH1 mutation, could first be screened for a BRAF mutation. BRAF-positive samples need not be further tested by MLH1 sequencing. MLH1 gene methylation largely correlates with the presence of BRAF-V600E and in combination with BRAF testing can accurately separate Lynch from sporadic CRC in IHC MLH1-negative cases.
Various attempts have been made to identify which patients with colon cancer should undergo testing for MMR mutations, based primarily on family history and related characteristics using criteria such as the Amsterdam II criteria (low sensitivity but high specificity) and the Bethesda guidelines (better sensitivity but poorer specificity). While family history is an important risk factor and should not be discounted in counseling families, it has poor sensitivity and specificity for identifying Lynch syndrome. Based on this and other evidence, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group recommended testing all newly diagnosed patients with colorectal cancer for Lynch syndrome, using a screening strategy based on MSI or IHC (± BRAF) followed by sequencing in screen-positive patients. This recommendation includes genetic testing for the following types of patients:
Recently, novel deletions have been reported to affect the expression of the MSH2 MMR gene in the absence of a 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.
Separately from patients with EPCAM deletions, rare Lynch syndrome patients have been reported without detectable germline MMR mutations although IHC testing demonstrates a loss of expression of one of the MMR proteins. In at least some of these cases, research has identified germline ‘epimutations,’ i.e., methylation of promoter regions that control the expression of the MMR genes. Such methylation may be isolated, or in conjunction with a linked genetic alteration near the affected MMR gene. The germline epimutations may arise de novo, or may be heritable in either Mendelian or non-Mendelian fashion. This is distinct from some cases of MSI-high sporadic colorectal cancer wherein the tumor tissue may show MLH1 promotor methylation and IHC non-expression, but the same is not true of germline cells. Clinical testing for Lynch syndrome-related germline epimutations is not routine but may be helpful in exceptional cases. Epimutations as a cause of Lynch syndrome are described only for informational purposes; no policy statement is made regarding this testing.
Female patients with Lynch syndrome have a predisposition to endometrial cancer. Lynch syndrome is estimated to account for 2% of all endometrial cancers in women and 10% of endometrial cancers in women younger than 50 years of age. Female carriers of the germline mutations MLH1, MSH2, MSH6, and PMS2 have an estimated 40-62% lifetime risk of developing endometrial cancer, as well as a 4-12% lifetime risk of ovarian cancer.
None of the tests reviewed in this policy are approved by the U.S. Food and Drug Administration (FDA). Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of CLIA. Genetic tests reviewed in this policy are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, FDA does not require regulatory review of these tests.
POLICYGenetic testing for APC gene mutations may be considered medically necessary in the following patients:
Genetic testing for APC gene mutations is not medically necessary for colorectal cancer patients with classical FAP for confirmation of the FAP diagnosis.
Genetic testing for MUTYH gene mutations may be considered medically necessary in the following patients:
Genetic testing for MMR gene mutations may be considered medically necessary in the following patients:
Genetic testing for EPCAM mutations may be considered medically necessary in the following patients:
Genetic testing for BRAF V600E or MLH1 promoter methylation may be considered medically necessary to exclude a diagnosis of Lynch syndrome when MLH1 protein is not expressed in a colorectal cancer on immunohistochemical (IHC) analysis.
Pre- and post-genetic counseling may be considered medically necessary as an adjunct to the genetic testing itself.
Genetic testing for all other gene mutations for Lynch syndrome or colorectal cancer is considered investigational.
POLICY GUIDELINESDue to the high lifetime risk of cancer of the majority of the genetic syndromes discussed in this policy, “at-risk relatives” primarily refers to first-degree relatives. However, some judgment must be allowed, for example, in the case of a small family pedigree, when extended family members may need to be included in the testing strategy.
It is recommended that, when possible, initial genetic testing for FAP or Lynch syndrome 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.
In many cases, genetic testing for MUTYH gene mutations should first target the specific mutations Y165C and G382D, which account for more than 80% of mutations in Caucasian populations, and subsequently proceed to sequencing only as necessary. In other ethnic populations, however, proceeding directly to sequencing is appropriate.
For patients with colorectal cancer being evaluated for Lynch syndrome, either the microsatellite instability (MSI) test, or the immunohistochemistry (IHC) test with or without BRAF gene mutation testing, should be used as an initial evaluation of tumor tissue prior to MMR gene analysis. Both tests are not necessary. Consideration of proceeding to MMR gene sequencing would depend on results of MSI or IHC testing. IHC testing in particular may help direct which MMR gene likely contains a mutation, if any, and may also provide some additional information if MMR genetic testing is inconclusive.
When indicated, genetic sequencing for MMR gene mutations should begin with MLH1 and MSH2 genes unless otherwise directed by the results of IHC testing. Standard sequencing methods will not detect large deletions or duplications; when MMR gene mutations are expected based on IHC or MSI studies but none are found by standard sequencing, additional testing for large deletions or duplications is appropriate.
The COLARIS® test from Myriad Genetic Laboratories includes sequence analysis of MLH1, MSH2, MSH6 and PMS2; large rearrangement analysis for MLH1 MSH2, PMS2, and MSH6 large deletions/duplications; and analysis for large deletions in the EPCAM gene near MSH2. Note that there may be 2 versions of this test, the COLARIS (excludes PMS2 testing) and COLARIS Update (includes PMS2 testing). Testing is likely done in stages, beginning with the most common types of mutations. Individualized testing (e.g., targeted testing for a family mutation) can also be requested.
The COLARIS® AP test from Myriad Genetic Laboratories includes DNA sequencing analysis of the APC and MUTYH genes, as well as analysis of large rearrangements in the APC gene that are not detected by DNA sequencing.
Amsterdam II Clinical Criteria (all criteria must be fulfilled). The Amsterdam criteria are the most stringent criteria for defining families at high risk for Lynch syndrome:
Revised Bethesda Guidelines (fulfillment of any criterion meets guidelines). The Bethesda guidelines are less strict than the Amsterdam criteria and are intended to increase the sensitivity of identifying at-risk families. The Bethesda guidelines are also felt to be more useful in identifying which patients with colorectal cancer should have their tumors tested for microsatellite instability and/or immunohistochemistry:
Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY2/20/2007: Policy added
3/22/2007: Reviewed and approved by the Medical Policy Advisory Committee (MPAC)
12/19/2007: Coding updated per the 2008 CPT/HCPCS revisions
9/15/2008: Code reference section updated per the annual ICD-9 updates effective 10-1-2008
12/24/2008: Code reference section updated per the 2009 CPT/HCPCS revisions
04/16/2010: Policy description, guidelines, and statements rewritten extensively due to new research findings and approaches to this genetic testing. Policy statements changed to indicate that testing the index patient with APC is considered not medically necessary. Intent of other policy statements generally unchanged, although requirement for positive family history no longer required for testing. Added ICD-9 code 154.0.
02/24/2012: Add policy statement regarding medically necessary indication for testing for EPCAM mutations in patients with colorectal cancer and negative MMR mutations. Policy description and guidelines updated regarding recent research findings and available testing. Added new CPT codes 81292-81294, 81295-81297, 81298-81300, 81301, and 81317-81319 to the Covered Codes table.
01/10/2013: Updated the policy description and policy guidelines to include criteria regarding Lynch syndrome-related endometrial cancer. Policy title changed from "Genetic Testing for Inherited Susceptibility to Colon Cancer Including Microsatellite Instability" to "Genetic Testing for Lynch Syndrome and Other Inherited Intestinal Polyposis Syndromes." Added the following policy statement: Patients with endometrial cancer and one first-degree relative diagnosed with a Lynch-associated cancer for the diagnosis of Lynch syndrome. Added ICD-9 code 182.0 to the Code Reference section. Added the following new 2013 CPT codes to the Code Reference section: 81201, 81202, and 81203.
08/01/2013: Added the following diagnosis codes to the Code Reference section. 151.0 - 151.9, 152.0 - 152.9, 157.0 - 157.9, 182.1 - 182.8, 183.0, 188.0 - 188.9, 189.1, 189.2, and V18.51.
04/07/2014: Policy title changed from “Genetic Testing for Lynch Syndrome and Other Inherited Intestinal Polyposis Syndromes” to “Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes.” Policy description updated to add new percentages for Lynch syndrome. Policy statement updated to include MLH1, PMS2, and MSH6 in the patient criteria for genetic testing for EPCAM mutations. Added the following policy statement: Genetic testing for BRAF V600E or MLH1 promoter methylation may be considered medically necessary to exclude a diagnosis of Lynch syndrome when MLH1 protein is not expressed in a colorectal cancer on immunohistochemical (IHC) analysis. Additional statement added to indicate that genetic testing for all other gene mutations for Lynch syndrome or colorectal cancer is considered investigational. Removed deleted CPT Codes 83890 – 83894, 83896 – 83898, 83902 – 83909, 83912, 83914 and HCPCS Codes S3828 – S3831.
01/08/2015: Policy description updated regarding FAP and Lynch Syndrome. Policy statements updated to change "MYH-associated polyposis" to "MUTYH-associated polyposis." Added "for confirmation of the FAP diagnosis" to the policy statement regarding genetic testing for APC gene mutations. Policy guidelines updated regarding Amsterdam criteria and Bethesda guidelines.
08/28/2015: Medical policy revised to add ICD-10 codes. Code Reference section updated to add CPT code 81288. Removed deleted HCPCS codes S3833 and S3834.
SOURCE(S)Blue Cross Blue Shield Association Policy #2.04.08
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.