Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes

POLICY NUMBER

A.2.04.08

DESCRIPTION

Genetic testing is available for both those with and those at risk for various types of hereditary cancer. This policy evaluates genetic testing for hereditary colorectal cancer (CRC) and polyposis syndromes, including familial adenomatous polyposis (FAP), Lynch syndrome (formerly known as hereditary nonpolyposis colorectal cancer), MUTYH-associated polyposis (MAP), Lynch syndrome-related endometrial cancer, juvenile polyposis syndrome (JPS), and Peutz-Jeghers syndrome (PJS).

Hereditary Colorectal Cancers

Currently, two types of hereditary colorectal cancers are well-defined: familial adenomatous polyposis (FAP) and Lynch syndrome (formerly hereditary nonpolyposis colorectal cancer [CRC]). Lynch syndrome has been implicated in some endometrial cancers as well.

Familial Adenomatous Polyposis and Associated Variants

Familial adenomatous polyposis typically develops by age 16 years and can be identified by the appearance of hundreds to thousands of characteristic, precancerous colon polyps. If left untreated, all affected individuals will develop colorectal cancer. The mean age of colon cancer diagnosis in untreated individuals is 39 years. The condition accounts for about 1% of colorectal cancer and may also be associated with osteomas of the jaw, skull, and limbs; sebaceous cysts; and pigmented spots on the retina referred to as congenital hypertrophy of the retinal pigment epithelium. Familial adenomatous polyposis associated with these collective extra-intestinal manifestations is sometimes referred to as Gardner Syndrome. This condition may also be related to central nervous system tumors, referred to as Turcot syndrome.

Germline variants in the adenomatous polyposis coli (APC) gene, located on chromosome 5, are responsible for FAP and are inherited in an autosomal dominant manner. Variants in the APC gene result in altered protein length in about 80% to 85% of cases of FAP. A specific APC gene variant (I1307K) has been found in Ashkenazi Jewish descendants, which may explain a portion of the familial colorectal cancer occurring in this population.

A subset of FAP patients may have an attenuated form of FAP, typically characterized by fewer than 100 cumulative colorectal adenomas occurring later in life than in classical FAP. In the attenuated form of FAP, colorectal cancer occurs at an average age of 50 to 55 years, but the lifetime risk of colorectal cancer remains high (>70% by age 80 years). The risk of extra-intestinal cancer is also lower but cumulative lifetime risk remains high (>38%) compared with the general population. Only 30% or fewer of attenuated FAP patients have APC variants; some of these patients have variants in the MUTYH (formerly MYH) gene, and this form of the condition is called MUTYH-associated polyposis (MAP). This form of polyposis occurs with a frequency similar to FAP, with some variability among prevalence estimates for both. While clinical features of MAP are similar to FAP or attenuated FAP, a strong multigenerational family history of polyposis is absent. Biallelic MUTYH variants are associated with a cumulative colorectal cancer risk of about 80% by age 70, whereas the monoallelic MUTYH variant-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 variants, and screening for variants 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 by syndrome.

Testing

Genetic testing for APC variants may be considered in the following situations:

• Patients at high-risk such as those with a family member who tested positive for FAP and have a known APC variant.

• Patients undergoing differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome. These patients do not meet the clinical diagnostic criteria for classical FAP and have few adenomatous colonic polyps.

• To confirm FAP in patients with colon cancer with a clinical picture or family history consistent with classical FAP.

Lynch syndrome

Lynch syndrome is an inherited disorder that results in a higher predisposition to colorectal cancer and other malignancies including endometrial and gastric cancer. Lynch syndrome is estimated to account for 3% to 5% of all CRC. People with Lynch syndrome have a 70% to 80% lifetime risk of developing any type of cancer. However, the risk varies by genotype. It occurs as a result of germline variants in the mismatch repair (MMR) genes that include MLH1, MSH2, MSH6, and PMS2. In approximately 80% of cases, the variants are located in the MLH1 and MSH2 genes, while 10% to 12% of variants are located in the MSH6 gene and 2% to 3% in the PMS2 gene. Additionally, variants in three additional genes (MLH3, PMS1, EX01) have been implicated with Lynch Syndrome. Notably, in individuals meeting the various clinical criteria for Lynch syndrome, 50% of individuals have a variant in the MLH1, MSH2, MSH6, and PMS2 genes. The lifetime risk of CRC is nearly 80% in individuals carrying a variant in one of these genes.

Testing

Preliminary screening of tumor tissue does not identify MMR gene variants but is used to guide subsequent diagnostic testing via DNA analysis for specific variants. Genetic testing or DNA analysis (gene sequencing, deletion, and duplication testing) for the MMR genes involves assessment for MLH1, MSH2, MSH6, and PMS2 variants. The following are three testing strategies.

1. Microsatellite instability (MSI) testing (phenotype): Individuals with high MSI either proceed to genetic testing for MLH1, MSH2, MSH6, and PMS2 or to immunohistochemical (IHC) testing.

2. IHC testing (phenotype): Individuals with negative staining would proceed to genetic testing for MLH1, MSH2, MSH6, and PMS2.

3. Modification strategy: Tumor tissue of patients with negative staining for MLH1 on IHC is tested for the BRAF V600E variant to determine methylation status. If the BRAF variant is not detected, the individual receives MLH1 DNA analysis.

The phenotype tests used to identify individuals who may be at a high-risk of Lynch syndrome are explained next. The first screening test measures MSI. As a result of variance in the MMR gene family, the MMR protein is either absent or deficient, resulting in an inability to correct DNA replication errors causing MSI. Approximately 80% to 90% of Lynch syndrome CRC tumors have MSI. The National Cancer Institute has recommended screening for 5 markers to detect MSI (Bethesda markers). Microsatellite instability detection in two of these markers is considered a positive result or “high probability of MSI.”

The second phenotype screening test is IHC, which involves the staining of tumor tissue for the presence of 4 MMR proteins (MLH1, MSH2, MSH6, PMS2). The absence of one or more of these proteins is considered abnormal.

BRAF testing is an optional screening method that may be used in conjunction with IHC testing for MLH1 to improve efficiency. Methylation analysis of the MLH1 gene can largely substitute for BRAF testing, or be used in combination to improve efficiency slightly.

Both MSI and IHC have a 5% to 10% false-negative rate. Microsatellite instability testing performance depends on the specific MMR variant. Screening with MSI has a sensitivity of about 89% for MLH1 and MSH2 and 77% for MSH6 and a specificity of about 90% for each. The specificity of MSI testing is low because approximately 10% of sporadic CRCs are MSI-positive due to somatic hypermethylation of the MLH1 promoter. Additionally, some tumors positive for MSH6 variants are associated with the MSI-low phenotype rather than MSI-high; thus MSI-low should not be a criterion against proceeding to MMR variant testing. Immunohistochemical screening has sensitivity for MLH1, MSH2, and MSH6 of about 83% and a specificity of about 90% for each.

Screening of tumor tissue from patients enables genetic testing for a definitive diagnosis of Lynch syndrome and leads to counseling, cancer surveillance (eg, through frequent colonoscopic or endometrial screening examinations), and prophylaxis (eg, risk-reducing colorectal or gynecologic surgeries) for CRC patients, as well as for their family members.

Genetic testing for an MMR gene variant is often limited to MLH1 and MSH2 and, if negative, then MSH6 and PMS2. The BRAF gene is often mutated in CRC when a particular BRAF variant (V600E, a change from valine to glutamic acid at amino acid position 600 in the BRAF protein) is present. To date, no MLH1 gene variants have been reported. Therefore, patients negative for MLH1 protein expression by IHC, and therefore potentially positive for an MLH1 variant, could first be screened for a BRAF variant. 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.

Novel deletions have been reported to affect the expression of the MSH2 gene in the absence of an MSH2 gene variant, 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 testing shows a lack of MSH2 expression, but no MSH2 variant is found by sequencing. EPCAM is found just upstream, in a transcriptional sense, of MSH2. Deletions of EPCAM that encompass the last 2 exons of the EPCAM gene, including the polyadenylation signal that normally ends transcription of DNA into messenger RNA, result in transcriptional “read-through” and subsequent hypermethylation of the nearby and downstream MSH2 promoter. This hypermethylation prevents normal MSH2 protein expression and leads to Lynch syndrome in a fashion similar to Lynch cases in which an MSH2 variant prevents MSH2 gene expression.

Distinct from patients with EPCAM deletions, rare cases of Lynch syndrome have been reported without detectable germline MMR variants, although IHC testing demonstrated a loss of expression of one of the MMR proteins. In at least some of these cases, research has identified germline "epivariants," i.e., methylation of promoter regions that control the expression of the MMR genes. Such methylation may be isolated or be in conjunction with a linked genetic alteration near the affected MMR gene. The germline epivariants may arise de novo or may be heritable in 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 epivariants is not routine but may help in exceptional cases.

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 variants MLH1, MSH2, MSH6, and PMS2 have an estimated 40% to 62% lifetime risk of developing endometrial cancer, as well as a 4% to 12% lifetime risk of ovarian cancer.

Population Selection

Various attempts have been made to identify which patients with colon cancer should undergo testing for MMR variants, based primarily on family history and related characteristics using criteria such as the Amsterdam II criteria (low sensitivity but high specificity), revised Bethesda guidelines (better sensitivity but poorer specificity), and risk prediction models (eg, MMRpro; PREMM5; MMRpredict). 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 Working Group recommended testing all newly diagnosed colorectal cancer patients for Lynch syndrome, using a screening strategy based on MSI or IHC (with or without BRAF) followed by sequencing in screen-positive patients. This recommendation includes genetic testing for the following types of patients:

• Family members of Lynch syndrome patients with a known MMR variant; family members would be tested only for the family variant; those testing positive would benefit from early and increased surveillance to prevent future colorectal cancer.

• Patients with a differential diagnosis of Lynch syndrome vs attenuated FAP vs. MUTYH-associated polyposis. 

• For Lynch syndrome patients, 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, benefitting family members by identifying the family variant.

Juvenile Polyposis Syndrome

Juvenile polyposis syndrome (JPS) is an autosomal dominant genetic disorder characterized by the presence of multiple hamartomatous (benign) polyps in the digestive tract. It is rare, with an estimated incidence of 1 in 100,000 to 160,000. Generalized juvenile polyposis refers to polyps in the upper and lower gastrointestinal tract, and juvenile polyposis coli refers to polyps of the colon and rectum. Those with JPS are at a higher risk for colorectal and gastric cancer. Approximately 60% of patients with JPS have a germline variant in the BMPR1A gene or the SMAD4 gene. Approximately 25% of patients have de novo variants. In most cases, polyps appear in the first decade of life and most patients are symptomatic by age 20 years. Rectal bleeding is the most common presenting symptom, occurring in more than half of patients. Other presenting symptoms include prolapsing polyp, melena, pain, iron deficiency anemia, and diarrhea.

As noted, individuals with JPS are at increased risk for colorectal and gastric cancer. By 35 years of age, the cumulative risk of CRC is 17% to 22%, which increases to 68% by age 60 years. The estimated lifetime risk of gastric cancer is 20% to 30%, with a mean age at diagnosis of 58 years. Juvenile polyposis syndrome may also be associated with hereditary hemorrhagic telangiectasia. The most common clinical manifestations of hereditary hemorrhagic telangiectasia are telangiectasias of the skin and buccal mucosa, epistaxis, and iron deficiency anemia from bleeding.

DiagnosisA clinical diagnosis of JPS is made on the basis of the presence of any one of the following: at least 5 juvenile polyps in the colon or multiple juvenile polyps in other parts of the gastrointestinal tract or any number of juvenile polyps in a person with a known family history of juvenile polyps. It is recommended that individuals who meet clinical criteria for JPS undergo genetic testing for a germline variant in the BMPR1A and SMAD4 genes for a confirmatory diagnosis of JPS and to counsel at-risk family members. If there is a known SMAD4 variant in the family, genetic testing should be performed within the first 6 months of life due to hereditary hemorrhagic telangiectasia risk.

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome (PJS) is also an autosomal dominant genetic disorder, similar to JPS, and is characterized by the presence of multiple hamartomatous (benign) polyps in the digestive tract, mucocutaneous pigmentation, and an increased risk of gastrointestinal and nongastrointestinal cancers. It is rare, with an estimated incidence of 1 in 8,000 to 200,000. In most cases, a germline variant in the STK11 (LKB1) gene is responsible for PJS, which has a high penetrance of over 90% by the age of 30 years. However, 10% to 20% of individuals with PJS have no family history and are presumed to have PJS due to de novo variants. A variant in STK11 is detected in only 50% to 80% of families with PJS, suggesting that there is a second PJS gene locus.

The reported lifetime risk for any cancer is between 37% and 93% among those diagnosed with PJS with an average age of cancer diagnosis at 42 years. The most common sites for malignancy are colon and rectum, followed by breast, stomach, small bowel, and pancreas. The estimated lifetime risk of gastrointestinal cancer ranges from 38% to 66%. Lifetime cancer risk stratified by organ site is colon and rectum (39%), stomach (29%), small bowel (13%), and pancreas (11% to 36%).

DiagnosisA clinical diagnosis of PJS is made if an individual meets two or more of the following criteria: presence of two or more histologically confirmed PJ polyps of the small intestine or characteristic mucocutaneous pigmentation of the mouth, lips, nose, eyes, genitalia, fingers, or family history of PJS. Individuals who meet clinical criteria for PJS should undergo genetic testing for a germline variant in the STK11 gene for a confirmatory diagnosis of PJS and counseling at-risk family members.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Genetic tests reviewed in this policy are available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

POLICY

APC Testing

Genetic testing of the APC gene may be considered medically necessary in the following individuals:

• At-risk relatives (see Policy Guidelines) of individuals with familial adenomatous polyposis (FAP) and/or a known APC variant.

• Individuals with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs Lynch syndrome. Whether testing begins with APC variants or screening for mismatch repair (MMR) variants depends on clinical presentation.

Genetic testing for APC gene variants is considered investigational for colorectal cancer (CRC) individuals with classical FAP for confirmation of the FAP diagnosis.

Testing for germline APC gene variants for inherited CRC syndromes is considered investigational in all other situations.

MUTYH Testing

Genetic testing of the MUTYH gene may be considered medically necessary in the following individuals:

• Individuals with a differential diagnosis of attenuated FAP vs MUTYH-associated polyposis vs Lynch syndrome and a negative result for APC gene variants. A family history of no parents or children with FAP is consistent with MUTYH-associated polyposis (autosomal recessive).

Testing for germline MUTYH gene variants for inherited CRC syndromes is considered investigational in all other situations.

MMR Gene Testing

Genetic testing of MMR genes (MLH1, MSH2, MSH6, PMS2) may be considered medically necessary in the following individuals:

• Individuals with colorectal cancer with tumor testing suggesting germline MMR deficiency or meeting clinical criteria for Lynch syndrome (See Policy Guidelines Section).

• Individuals with endometrial cancer with tumor testing suggesting germline MMR deficiency or meeting clinical criteria for Lynch syndrome (see Policy Guidelines section).

• At-risk relatives (see Policy Guidelines) of individuals with Lynch syndrome with a known pathogenic/likely pathogenic MMR gene variant.

• Individuals with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome. Whether testing begins with APC variants or screening for MMR genes depends on clinical presentation.

• Individuals without colorectal cancer but with a family history meeting the Amsterdam or Revised Bethesda criteria, or documentation of 5% or higher predicted risk of the syndrome on a validated risk prediction model (e.g. MMRpro, PREMM5 or MMRpredict), when no affected family members have been tested for MMR variants.

Testing for germline MMR gene variants for inherited CRC syndromes is considered investigational in all other situations.

EPCAM Testing

Genetic testing of the EPCAM gene may be considered medically necessarywhen any 1 of the following 3 major criteria (solid bullets) is met:

• Individuals with colorectal cancer, for the diagnosis of Lynch syndrome (see Policy Guidelines) when:

  • Tumor tissue shows lack of MSH2 protein expression by immunohistochemistry and individual is negative for an MSH2 germline variant; or

  • Tumor tissue shows a high level of microsatellite instability and individual is negative for a germline variant in MLH1, MSH2, MSH6, and PMS2; OR

• At-risk relatives (see Policy Guidelines) of individuals with Lynch syndrome with a known pathogenic/likely pathogenic EPCAM variant; OR

• Individuals without colorectal cancer but with a family history meeting the Amsterdam or Revised Bethesda criteria, or documentation of 5% or higher predicted risk of the syndrome on a validated risk prediction model (e.g. MMRpro, PREMM5 or MMRpredict), when no affected family members have been tested for MMR variants, and when sequencing for MMR variants is negative.

Testing for germline EPCAM gene variants for inherited CRC syndromes is considered investigational in all other situations.

BRAFV600E or MLH1 Promoter Methylation

Somatic 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 tumor on immunohistochemical (IHC) analysis.

Testing for somatic BRAF V600E or MLH1 promoter methylation to exclude a diagnosis of Lynch syndrome is considered investigational in all other situations.

SMAD4 and BMPR1A Testing

Genetic testing of SMAD4 and BMPR1A genes may be considered medically necessary when any one of the following major criteria (solid bullets) is met:

• Individuals with a clinical diagnosis of juvenile polyposis syndrome based on the presence of any one of the following:

  • at least 5 juvenile polyps in the colon

  • multiple juvenile polyps found throughout the gastrointestinal tract

  • any number of juvenile polyps in a person with a known family history of juvenile polyps.

• At-risk relative of an individual suspected of or diagnosed with juvenile polyposis syndrome.

Testing for germline SMAD4 and BMPR1A gene variants for inherited CRC syndromes is considered investigational in all other situations.

STK11 Testing

Genetic testing for STK11 gene variants may be considered medically necessary when any one of the following major criteria (solid bullets) is met:

• Individuals with a clinical diagnosis of Peutz-Jeghers syndrome based on the presence of any 2 of the following:

  • presence of 2 or more histologically confirmed Peutz-Jeghers polyps of the gastrointestinal tract.

  • characteristic mucocutaneous pigmentation of the mouth, lips, nose, eyes, genitalia, or fingers.

  • family history of Peutz-Jeghers syndrome.

• At-risk relative of an individual suspected of or diagnosed with Peutz-Jeghers syndrome.

Testing for germline STK11 gene variants for inherited CRC syndromes is considered investigational in all other situations.

Other Variants

Genetic testing of all other genes for an inherited CRC syndrome is considered investigational.

Genetic Counseling

Pre- and post test genetic counseling may be considered medically necessary as an adjunct to the genetic testing itself.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Testing At-Risk Relatives

Due to the high lifetime risk of cancer of most genetic syndromes discussed in this policy, “at-risk relatives” primarily refers to first-degree relatives. However, some judgment must be permitted, for example, in the case of a small family pedigree, when extended family members may need to be included in the testing strategy. A family history might include at least 2 second-degree relatives with a Lynch syndrome-related cancer, including at least 1 diagnosed before 50 years of age, or at least 3 second-degree relatives with a Lynch syndrome-related cancer, regardless of age.

Targeted Familial Variant Testing

It is recommended that, when possible, initial genetic testing for familial adenomatous polyposis or Lynch syndrome be performed in an affected family member so that testing in unaffected family members can focus on the variant found in the affected family member. If an affected family member is not available for testing, testing should begin with an unaffected family member most closely related to an affected family member.

In many cases, genetic testing for MUTYH gene variants should first target the specific variants Y165C and G382D, which account for more than 80% of variants in white populations, and subsequently, proceed to sequence only as necessary. However, in other ethnic populations, proceeding directly to sequencing is appropriate.

Evaluation for Lynch Syndrome

For patients with colorectal cancer (CRC) or endometrial cancer being evaluated for Lynch syndrome, the microsatellite instability (MSI) test, or the immunohistochemistry (IHC) test with or without BRAF gene variant testing, or methylation testing, should be used as an initial evaluation of tumor tissue before mismatch repair (MMR) gene analysis. Both tests are not necessary. Proceeding to MMR gene sequencing would depend on the results of MSI or IHC testing. In particular, IHC testing may help direct which MMR gene likely contains a variant, if any, and may also provide additional information if MMR genetic testing is inconclusive. For further information on tumor tissue test results, interpretation, and additional testing options, see the NCCN [National Comprehensive Cancer Network] clinical care guidelines on genetic/familial high-risk assessment: colorectal.

When indicated, genetic sequencing for MMR gene variants 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 variants 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 Amsterdam II Clinical Criteria (all criteria must be fulfilled) are the most stringent criteria for defining families at high risk for Lynch syndrome:

• 3 or more relatives with an associated cancer (colorectal cancer, or cancer of the endometrium, small intestine, ureter or renal pelvis);

• 1 should be a first-degree relative of the other two;

• 2 or more successive generations affected;

• 1 or more relatives diagnosed before the age of 50 years;

• Familial adenomatous polyposis (FAP) should be excluded in cases of colorectal carcinoma;

• Tumors should be verified by pathologic examination.

• Modifications:

  • EITHER: very small families, which cannot be further expanded, can be considered to have hereditary nonpolyposis colorectal cancer (HNPCC) with only two colorectal cancers in first-degree relatives if at least two generations have the cancer and at least one case of colorectal cancer was diagnosed by the age of 55 years;

  • OR: in families with two first-degree relatives affected by colorectal cancer, the presence of a third relative with an unusual early-onset neoplasm or endometrial cancer is sufficient.

The Revised Bethesda Guidelines (fulfillment of any criterion meets guidelines) are less stringent than the Amsterdam criteria and are intended to increase the sensitivity of identifying at-risk families. The Bethesda guidelines are also considered more useful in identifying which patients with colorectal cancer should have their tumors tested for microsatellite instability and/or immunohistochemistry:

• Colorectal carcinoma (CRC) diagnosed in a patient who is younger than 50 years old;

• Presence of synchronous (at the same time) or metachronous (at another time i.e.- a recurrence of) CRC or other HNPCC-associated tumors,* regardless of age;

• CRC with high microsatellite instability histology diagnosed in a patient younger than 60 years old;

• CRC diagnosed in one or more first-degree relatives with a Lynch syndrome-associated tumor, with one of the cancers being diagnosed before 50 years of age;

• CRC diagnosed in two or more first or second-degree relatives with HNPCC-related tumors,* regardless of age.

*HNPCC-related tumors include colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, brain (usually glioblastoma as seen in Turcot syndrome), sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel.

Multiple risk prediction models that provide quantitative estimates of the likelihood of an MMR variant are available such MMRpro, PREMM5, or MMRpredict. National Comprehensive Cancer Network guidelines recommend (category 2A) testing for Lynch syndrome in individuals with a 5% or higher predicted risk of the syndrome on these risk prediction models.

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

2/20/2007: 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.

02/15/2016: Policy description updated. Policy statements unchanged. Policy guidelines updated regarding laboratories that provide mutation testing. Added genetic counseling information and medically necessary and investigative definitions.

03/30/2016: Policy description updated. Policy statements unchanged. Policy guidelines updated regarding tests and to update criteria for the Bethesda Guidelines.

06/06/2016: Policy number A.2.04.08 added.

09/29/2017: Code Reference section updated to remove ICD-10 diagnosis code Z31.5 and ICD-9 diagnosis code V26.33.

10/12/2017: Policy updated to change "mutations" to "variants" throughout the policy. Policy description updated regarding Lynch syndrome and testing. Policy section updated to add headings, list MMR genes, change "MSH2 expression" to "MSH2 protein expression," and to change "colorectal cancer" to "colorectal cancer tumor." Policy Guidelines updated to add genetics nomenclature update. Code Reference section updated to add CPT codes 81210 and 81403.

12/22/2017: Code Reference section updated to revise description for CPT code 81403 effective 01/01/2018.

02/01/2019: Policy description updated to add information regarding juvenile polyposis syndrome and Peutz-Jeghers syndrome. Added policy statements that genetic testing for SMAD4, BMPR1A, and STK11 gene variants may be considered medically necessary when any one of the listed criteria is met. Policy Guidelines updated to revise genetic counseling information. Code Reference section updated to add CPT codes 81435 and 81436.

12/20/2019: Code Reference section updated to add new CPT codes 0157U, 0158U, 0159U, 0160U, 0161U, and 0162U effective 01/01/2020.

06/23/2020: Policy description updated. Policy statements for MMR Gene Testing and EPCAM Testing updated to include criteria for individuals with documentation of 5% or higher predicted risk of the syndrome of a validated risk prediction model (e.g. MMRpro, PREMM5 or MMRpredict). Link in Policy Guidelines updated.

12/17/2020: Code Reference section updated to add new CPT code 0238U, effective 01/01/2021.

01/08/2021: Policy statement criteria regarding SMAD4 and BMPR1A testing updated to change "3 to 5 juvenile polyps" to "5 juvenile polyps." Policy statement criteria regarding STK11 testing updated to change "small intestine" to "gastrointestinal tract." Policy statement regarding genetic counseling updated to change "post-genetic counseling" to "post test genetic counseling." Policy Guidelines updated regarding testing at-risk relatives. Removed information regarding CLIA-licensed laboratories offering MMR gene and APC variant testing. Removed information regarding genetics nomenclature.

04/13/2022: Policy description updated with minor changes. Policy statement criteria for MMR gene testing updated for clarification to include "with tumor testing suggesting germline MMR deficiency or meeting clinical criteria." Added policy statements that all other situations are considered investigational. Policy Guidelines updated regarding targeted familial variant testing and evaluation for Lynch Syndrome.

11/10/2022: Policy description updated. Policy statements unchanged. Policy Guidelines updated regarding genetic counseling.

09/29/2023: Code Reference section updated to add new ICD-10 diagnosis codes D13.91, Z83.710, Z83.711, Z83.718, and Z83.719, effective 10/01/2023.

10/10/2023: Policy reviewed. Policy statements updated to change "patients" to "individuals" and "not medically necessary" to "investigational." Policy Guidelines updated.

10/01/2024: Code Reference section updated to add new ICD-10 diagnosis codes Z83.72, Z86.0100, Z86.0101, Z86.0102, and Z86.0109. Removed deleted ICD-10 diagnosis code Z83.71.

11/08/2024: Policy description updated with minor changes. Policy statements unchanged. Policy Guidelines updated with minor changes.

12/31/2024: Code Reference section updated to revise description for CPT code 81435 effective 01/01/2025.

10/01/2025: Code Reference section updated to revise description for ICD-10 diagnosis code Z83.718.

SOURCE(S)

Blue Cross Blue Shield Association Policy #2.04.08

CODE REFERENCE

This 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.

Covered Codes

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