CurrentCapital BluecrossPolicy MP 5.013

Genetic testing for Lynch syndrome and other inherited colon cancer syndromes

Covers when germline and select somatic genetic tests for Lynch syndrome and other inherited colorectal cancer syndromes (e.g., APC, MUTYH, MMR genes, EPCAM, SMAD4, BMPR1A, STK11, and select somatic tests) are considered medically necessary or investigational for Capital BlueCross members.

Policy Summary

PayerCapital Bluecross

PolicyGenetic testing for Lynch syndrome and other inherited colon cancer syndromes

Policy CodePolicy MP 5.013

Change TypeAdministrative / coding updates

Effective DateOct 1, 2025

Next Review Date

Key ActionPerform tumor MSI or IHC testing (with BRAF V600E or MLH1 methylation as applicable) before ordering germline MMR gene analysis for patients with colorectal or endometrial cancer.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

MP 5.013Policy number

pre/post-testGenetic counseling

≥5%Risk threshold

Y165C/G382DTargeted MUTYH variants

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Coverage Criteria for Genetic Testing

APC testing

APC gene testing — Covered when ANY of the following are met

APC_covered: At-risk relatives of individuals with familial adenomatous polyposis (FAP) and/or a known APC variant; OR individuals with a differential diagnosis of attenuated FAP vs MUTYH-associated polyposis (MAP) vs Lynch syndrome (selection of APC vs MMR testing depends on clinical presentation).

Genetic testing for APC is investigational for confirmation of classical FAP and investigational in other situations.

MUTYH testing

MUTYH gene testing — Covered when ALL of the following are met

MUTYH_covered: Individuals with a differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome AND a negative APC result; family history consistent with autosomal recessive inheritance (for example, no parents or children with FAP).

Initial targeted testing for MUTYH Y165C and G382D variants may be appropriate in white populations; sequencing may be needed in other populations.

MMR gene testing

Germline MMR gene testing — Covered when ANY of the following are met

MMR_covered: Individuals with colorectal cancer (CRC) or endometrial cancer whose tumor testing suggests germline MMR deficiency (MSI and/or absent MMR protein on IHC) or who meet clinical criteria for Lynch syndrome; at-risk relatives of individuals with a known pathogenic/likely pathogenic MMR variant; individuals without CRC but with family history meeting Amsterdam or Revised Bethesda criteria or with ≥5% predicted risk on a validated model (eg, MMRpro, PREMMs, MMRpredict) when no affected family members have been tested.>=5% predicted risk on validated models

Tumor MSI or IHC (with or without BRAF V600E or MLH1 promoter methylation) should be used as initial evaluation prior to germline MMR analysis; IHC may direct which MMR gene to sequence and deletion/duplication testing should follow if sequencing is negative but MMR deficiency is expected.

EPCAM testing

EPCAM testing — Covered when ANY of the following are met

EPCAM_covered: Individuals with CRC whose tumor shows loss of MSH2 expression by IHC or shows high microsatellite instability (MSI) and who are negative for germline MSH2, MLH1, PMS2, and MSH6 variants; individuals without CRC who meet Amsterdam or Revised Bethesda criteria or have ≥5% predicted risk on a validated model when no affected family members have been tested; and at-risk relatives of patients with a known EPCAM variant.>=5% predicted risk on validated models

Germline EPCAM testing is investigational in other situations.

Somatic BRAF V600E / MLH1 methylation

Somatic testing to exclude Lynch syndrome — Covered when ANY of the following are met

Somatic_exclusion: Somatic testing for BRAF V600E or MLH1 promoter methylation when MLH1 protein is not expressed in a colorectal tumor on IHC to help exclude Lynch syndrome.

Positive BRAF V600E or MLH1 promoter methylation suggests sporadic CRC and may obviate further germline MLH1 testing; somatic testing for these targets is investigational for other indications.

SMAD4 and BMPR1A testing

SMAD4 and BMPR1A testing — Covered when ANY of the following are met

SMAD4_BMPR1A_covered: Individuals with a clinical diagnosis of juvenile polyposis syndrome (JPS) defined by at least one of: multiple juvenile polyps in other parts of the GI tract; five or more juvenile polyps in the colon; or any juvenile polyps with a known family history of juvenile polyps; and at-risk relatives of an individual suspected of or diagnosed with JPS.

If a known SMAD4 family variant exists, testing may be recommended early in life due to associated hereditary hemorrhagic telangiectasia risk; germline testing is investigational in other situations.

STK11 testing

STK11 testing — Covered when ANY of the following are met

STK11_covered: Individuals with a clinical diagnosis of Peutz-Jeghers syndrome (PJS) defined by two or more of: characteristic mucocutaneous pigmentation, two or more histologically confirmed PJS polyps in the GI tract, or a family history of PJS.

Germline STK11 testing is investigational in other situations; testing of at-risk relatives is appropriate when a familial STK11 variant is known.

Other gene testing

Other genes

Other_genes_investigational: Genetic testing for all other gene variants for Lynch syndrome or colorectal cancer is considered investigational due to insufficient evidence.

Genetic counseling

Genetic_counseling: Pre-test and post-test genetic counseling by a qualified provider may be considered medically necessary as an adjunct to genetic testing for hereditary colorectal cancer syndromes; counseling is recommended for probands and family members to discuss implications for surveillance and management.

Documentation of counseling may be required as part of clinical documentation supporting testing.

Clinical indications and testing strategies

Testing for inherited colorectal cancer syndromes is described as appropriate in the following clinical scenarios:

Indications_for_APC_testing: APC testing may be considered for: (1) patients with a family member who tested positive for FAP with a known APC variant; (2) patients undergoing differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome who have few adenomatous polyps; (3) to confirm FAP in patients with colon cancer and a clinical picture or family history consistent with classical FAP.

Source: policy clinical indications

Indications_for_MUTYH_testing: MUTYH testing should be considered in patients with attenuated polyposis or when APC testing is negative and clinical features suggest MAP; distinguish monoallelic from biallelic variants because inheritance and management differ; targeted testing for common variants may be appropriate depending on ethnicity.

Source: policy clinical indications

Tumor_based_Lynch_screening: Initial tumor screening with MSI and/or IHC (with optional BRAF V600E testing or MLH1 promoter methylation analysis) is used to identify patients who should proceed to germline MMR gene testing; MSI-high or absent MMR protein expression on IHC indicates further genetic evaluation.

MMR gene testing (Lynch syndrome) coverage

Covered when ANY of the following clinical scenarios apply

MMR_testing_indications: Individuals suspected of attenuated FAP, MAP, and Lynch syndrome; individuals with colon or endometrial cancer with a first-degree relative diagnosed with a Lynch-associated cancer; at-risk relatives of patients with Lynch syndrome; individuals without colon cancer but with family history meeting Amsterdam or Revised Bethesda criteria; or documentation of ≥5% predicted risk on a validated model.>=5% predicted risk on validated models

Evidence supports clinical utility of MMR gene testing in these scenarios.

Tumor-directed reflex testing

Covered when tumor testing patterns indicate specific follow-up germline or somatic testing

EPCAM_followup: Individuals who screen negative on standard MMR germline testing but whose tumor shows microsatellite instability and loss of MSH2 protein expression may receive EPCAM genetic testing to identify deletions affecting MSH2 expression.

Identification of EPCAM variants can change management and is supported by evidence.

BRAF_MLH1_methylation_followup: Individuals with colorectal cancer in whom MLH1 protein is not expressed on IHC may receive testing for BRAF V600E or MLH1 promoter methylation to distinguish sporadic CRC from Lynch syndrome; positive results can obviate further germline MLH1 testing.

BRAF V600E and MLH1 promoter methylation testing have high sensitivity and specificity for sporadic MLH1 loss.

JPS and PJS testing

Covered when ALL of the following are met for JPS or PJS

JPS_clinical_criteria: Clinical diagnosis of juvenile polyposis syndrome made by: ≥5 juvenile polyps in the colon; multiple juvenile polyps elsewhere in the GI tract; or any juvenile polyps with a known family history. Individuals meeting these criteria should undergo genetic testing for BMPR1A and SMAD4.

If a known SMAD4 family variant exists, testing may be indicated early due to associated hereditary hemorrhagic telangiectasia risk.

PJS_clinical_criteria: Clinical diagnosis of Peutz-Jeghers syndrome made when two or more of: ≥2 histologically confirmed PJS polyps of the small intestine; characteristic mucocutaneous pigmentation; or family history of PJS. Individuals meeting criteria should undergo genetic testing for STK11.

Testing of at-risk relatives is appropriate when a familial STK11 variant is known.

FAP/MAP gene testing

Covered when testing informs differential diagnosis and management

APC_MUTYH_context: Individuals suspected of attenuated FAP, MUTYH-associated polyposis (MAP), or Lynch syndrome and at-risk relatives of patients with FAP; MUTYH testing is indicated after a negative APC result when MAP is in the differential and distinguishing the two syndromes would change surveillance or prophylactic management.

Targeted MUTYH variant testing may be appropriate depending on population; sequencing as needed.

Germline testing for genes discussed in this policy (including APC, MUTYH, EPCAM, MMR genes, SMAD4, BMPR1A, STK11 and others) is considered investigational when performed outside the specific clinical indications listed in this policy. The policy notes that testing for "all other gene variants" related to Lynch syndrome or inherited colorectal cancer syndromes lacks sufficient evidence to support clinical benefit and therefore is investigational in those circumstances.

When a colorectal tumor demonstrates loss of MLH1 protein expression by IHC, sequencing of germline MLH1 is generally not required if the tumor’s MLH1 loss is explained by a positive somatic BRAF V600E result or by MLH1 promoter hypermethylation. In such cases, the presence of BRAF V600E and/or MLH1 promoter methylation supports a sporadic etiology and can obviate further germline MLH1 sequencing.

Policy coverage statements describe circumstances in which testing may be considered medically necessary, but do not by themselves guarantee payment. Final coverage and claim adjudication remain subject to the member’s benefit plan, program-specific rules, and medical necessity determinations under the member’s contract.

Administrative coding updates in the policy history include additions and removals of specific procedure and diagnosis codes; for example, code 81436 was removed effective 01/01/2025. Providers should not rely on codes that have been administratively removed and must use current, effective codes when requesting authorization or submitting claims.

Use of germline genetic testing outside the indications defined in this policy (for example, testing APC, MUTYH, EPCAM, MMR genes, SMAD4/BMPR1A, STK11, or other listed genes when the clinical criteria are not met) is considered investigational / not medically necessary. Such testing may be denied if it does not align with the policy’s covered indications.

The presence of a procedure or diagnosis code in the coding section does not itself establish coverage. Services billed with listed codes may be denied if they do not meet the policy’s medical necessity criteria or the member’s benefit plan rules; coverage and reimbursement remain subject to member-specific benefit determinations.

Detailed Covered Indications

Tumor and clinical criteria for MMR testing

Tumor and clinical criteria for MMR testing — tumor MSI/IHC (± BRAF/MLH1 methylation) used prior to germline MMR analysis; applies to CRC or endometrial cancer patients, at-risk relatives, those meeting Amsterdam/Bethesda or >=5% risk

Tumor_screen_before_germline: Perform MSI testing or IHC (MLH1, MSH2, MSH6, PMS2) as initial tumor evaluation in patients with CRC or endometrial cancer; proceed to germline MMR gene sequencing and deletion/duplication testing for screen-positive patients. IHC results may direct which gene to sequence and BRAF V600E or MLH1 promoter methylation testing may triage MLH1 IHC-negative tumors.MSI positive = 2 of 5 Bethesda markers

Tumor-based screening is recommended prior to germline testing to improve efficiency and direct testing.

APC testing covered indications

APC testing covered indications — at-risk relatives of individuals with FAP or known APC variant; differential diagnosis scenarios

APC_indications_summary:

Investigational or Not Covered Services

Genetic testing for gene variants beyond those specifically addressed as covered in this policy is considered investigational and not covered due to insufficient evidence of clinical benefit. This includes testing for additional or atypical gene variants implicated in Lynch syndrome or colorectal cancer when they are not part of the covered indications.

Germline sequencing of MLH1 is generally unnecessary when tumor MLH1 loss by IHC is fully explained by a somatic BRAF V600E mutation or by MLH1 promoter methylation. In such scenarios, somatic testing that demonstrates BRAF V600E and/or MLH1 hypermethylation can distinguish sporadic CRC from Lynch syndrome and may obviate further germline MLH1 testing.

Listing of a billing or procedure code in the policy’s coding section is informational and does not guarantee coverage. Claims for services that are inconsistent with the member’s benefit plan or that are not medically necessary under the policy may be denied regardless of code listing.

Other tests or indications not explicitly described as covered in this policy are treated as not covered or investigational. This section serves as a placeholder to indicate that genetic testing beyond the stated covered indications is not supported by sufficient evidence and therefore not covered under the policy.

Procedure and Diagnosis Coding

Covered procedure codes (partial list)CPTCovered

0157U	Procedure code listed as covered when medically necessary
0158U	Procedure code listed as covered when medically necessary
0159U	Procedure code listed as covered when medically necessary
0160U	Procedure code listed as covered when medically necessary
0161U	Procedure code listed as covered when medically necessary
0162U	Procedure code listed as covered when medically necessary
0238U	Procedure code listed as covered when medically necessary
0474U	Procedure code listed as covered when medically necessary
81201	Procedure code listed as covered when medically necessary

Covered/Referenced procedure codes (continued)CPTCovered

81202	Procedure code listed
81203	Procedure code listed
81210	Procedure code listed
81288	Procedure code listed
81292	Procedure code listed
81293	Procedure code listed
81294	Procedure code listed
81295	Procedure code listed
81296	Procedure code listed
81297	Procedure code listed

1–10 of 19

1/2

ICD-10 codes and descriptionsICD-10

C18.0	Malignant neoplasm of cecum
C18.1	Malignant neoplasm of appendix
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
C18.9	Malignant neoplasm of colon, unspecified
C19	Malignant neoplasm of rectosigmoid junction

1–10 of 16

1/2

Policy history: added and removed codesmixed

0238U	Reference to added code in 2020/2021 (document history)
0474U	Code added effective 07/01/2024
0421U	Code removed (document history notes removal)
81436	Code removed effective 01/01/2025
D1391	Diagnosis code added to the policy
D1399	Diagnosis code added to the policy
Z15.060	ICD-10 code added effective 10/01/2025

Risk prediction model threshold — inv-26

Threshold>= 5% predicted risk on validated models (examples: MMRpro, PREMMs, MMRpredict)

ContextApplied when no affected family members have been tested and model-predicted risk meets or exceeds threshold

Recommended actionConsider germline MMR gene testing when model risk >=5%

MSI positivity (Bethesda markers) — inv-27

DefinitionMSI detection in 2 of 5 Bethesda markers is considered MSI-high (positive)

Use

Provider Actions and Documentation Requirements

Documentation Required

Tumor testing before germline MMR sequencing

For evaluation of colorectal or endometrial cancer when Lynch syndrome is a consideration, perform tumor-based screening (MSI or IHC, with BRAF V600E testing or MLH1 methylation analysis as applicable) as the initial test before proceeding to germline MMR gene sequencing. IHC results can direct which MMR gene(s) to sequence; MSI-high or abnormal IHC should prompt further germline testing per results. MSI-low does not rule out proceeding to MMR testing if clinical suspicion remains.

Stepwise approach: tumor phenotype testing → targeted germline MMR testing
Use BRAF V600E and/or MLH1 methylation to distinguish sporadic MLH1 loss from probable Lynch syndrome

Note

Policy applicability varies by product/program

This policy applies only to certain Capital BlueCross programs and products and may not apply to all lines of business (see product variations). Some products or programs (for example FEP PPO) reference alternative medical policy manuals and may have different prior authorization or coverage rules. Providers should verify product-specific requirements prior to ordering.

Eligibility Requirements and Scope

For policy purposes, "at-risk relatives" primarily refers to first-degree relatives of an affected individual but may extend to family structures described in the policy (for example, certain constellations of affected second-degree relatives) when those patterns meet clinical criteria. When the brief or specific chunk references are not available, readers should refer to the full policy text for the detailed family-history definitions and examples that guide who qualifies as an at-risk relative.

When evaluating polyposis phenotypes, testing is typically sequenced with APC analysis first and MUTYH testing following if APC is negative and the clinical picture suggests MUTYH-associated polyposis (MAP). Targeted MUTYH testing for common variants (e.g., Y165C, G382D) may be considered in appropriate populations, with sequencing used when targeted panels are insufficient. For full details and population-specific recommendations, refer to the policy’s testing sequencing guidance.

APC testing is generally the initial step for suspected familial adenomatous polyposis or attenuated polyposis; if APC testing is negative and MAP remains in the differential, MUTYH sequencing is appropriate. This sequencing approach aligns with the policy rationale that distinguishing FAP from MAP affects management and surveillance strategies.

Where the clinical presentation suggests attenuated FAP versus MUTYH-associated polyposis, providers should consider APC testing first and proceed to MUTYH testing if APC is negative. Documentation of the differential diagnosis and family history is recommended to support the sequencing decision.

Initial targeted MUTYH testing (for example, for Y165C and G382D) may be appropriate in certain populations; when targeted testing is negative or the population background differs, comprehensive MUTYH sequencing should be performed to evaluate for pathogenic variants.

Definitions and Terminology

Variant classification — inv-47

StandardsVariant classification uses ACMG-AMP standards for interpretation

NomenclatureHGVS (Human Genome Variation Society) nomenclature is used for reporting DNA variants

Standard termsReporting terms include: pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, benign

Amsterdam II and Revised Bethesda criteria — inv-48

PurposeAmsterdam II and Revised Bethesda are family-history based criteria to identify individuals/families at high risk for Lynch syndrome

Amsterdam II featuresStringent criteria: >=3 relatives with associated cancers across >=2 generations, one diagnosed <50, with pathologic verification

Background and Epidemiology

Lynch syndrome and other inherited colorectal cancer syndromes are caused by germline variants in mismatch repair genes and other genes such as MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH, SMAD4, BMPR1A, and STK11. Tumor phenotype testing with MSI and/or IHC for MMR proteins can identify mismatch repair deficiency and guide selection of subsequent germline testing. Risk prediction models and clinical criteria (e.g., Amsterdam II, Revised Bethesda) are used to identify individuals who warrant genetic evaluation.

Coding Guidance and Notes

Note

Risk prediction model threshold (coding guidance) — inv-26 callout

Threshold restatement>= 5% predicted risk on validated models (eg, MMRpro, PREMMs, MMRpredict) — reiterated in coding guidance

PurposeDuplicative callout to emphasize model-based eligibility when no affected family members tested

ActionUse validated risk models to document predicted risk when applying this threshold for testing decisions

Policy Revision History

Policy history: added and removed codesmixed

0238U	Reference to added code in 2020/2021 (document history)
0474U	Code added effective 07/01/2024
0421U	Code removed (document history notes removal)
81436	Code removed effective 01/01/2025
D1391	Diagnosis code added to the policy
D1399	Diagnosis code added to the policy
Z15.060	ICD-10 code added effective 10/01/2025

2025-09-02administrative_updateLatest

Added ICD-10 code Z15.060 to the policy, effective 10/01/2025.

2025-01-13consensus_review

Consensus review with minor editorial updates to the policy statement; removed code 0421U; references updated.

2024-12-10administrative_update

Policy Summary

PayerCapital Bluecross

PolicyGenetic testing for Lynch syndrome and other inherited colon cancer syndromes

Policy CodePolicy MP 5.013

Change TypeAdministrative / coding updates

Effective DateOct 1, 2025

Next Review Date

Key ActionPerform tumor MSI or IHC testing (with BRAF V600E or MLH1 methylation as applicable) before ordering germline MMR gene analysis for patients with colorectal or endometrial cancer.

SourceLink

On This Page

MSI positive = 2 of 5 Bethesda markers

Source: policy tumor screening section

Germline_MMR_testing_indications: Germline sequencing and deletion/duplication testing of MMR genes (MLH1, MSH2, MSH6, PMS2) is indicated for those with positive tumor screens, family members of probands with known pathogenic MMR variants (tested for the familial variant), and patients meeting clinical criteria or risk-model thresholds where Lynch is possible.>=5% predicted risk on validated models

Source: policy clinical indications

EPCAM_testing_indication: EPCAM deletion testing is appropriate when tumor screening shows MSI-high and/or loss of MSH2 expression by IHC but no MSH2 germline variant is found by sequencing.

Source: policy EPCAM section

JPS_testing_criteria: Individuals meeting clinical criteria for juvenile polyposis syndrome (≥5 juvenile polyps in the colon; multiple juvenile polyps elsewhere; or any juvenile polyps with family history) should undergo genetic testing for BMPR1A and SMAD4; if a known SMAD4 family variant exists, testing may be indicated early in life.

Source: policy JPS section

APC testing is appropriate for at-risk relatives of individuals with FAP or a known familial APC variant; for patients undergoing differential diagnosis of attenuated FAP versus MAP versus Lynch syndrome (especially those with few adenomatous polyps); and to confirm FAP in patients with clinical features or family history consistent with classical FAP.

APC testing is investigational for confirmation of classical FAP in most situations beyond these indications.

MUTYH testing covered indications

MUTYH testing covered indications — individuals suspected MAP after negative APC testing; targeted initial MUTYH testing for Y165C and G382D may be appropriate in white populations

MUTYH_indications_summary: Consider MUTYH testing for individuals with attenuated polyposis or when APC testing is negative and clinical features suggest MUTYH-associated polyposis (MAP). In white populations, initial targeted testing for Y165C and G382D variants is often appropriate, with sequencing if needed in other populations.

Family history consistent with autosomal recessive inheritance supports MUTYH testing.

EPCAM / MMR-related covered indications

EPCAM / MMR-related covered indications — individuals with CRC whose tumor shows loss of MSH2 expression by IHC or high MSI and negative for germline MMR genes; family-history based indications; at-risk relatives of known EPCAM variant carriers

EPCAM_MMR_indications: EPCAM testing is indicated for CRC patients whose tumor shows loss of MSH2 expression by IHC or high MSI and who are negative for germline MMR gene variants; it is also indicated for individuals meeting Amsterdam/Bethesda criteria or ≥5% predicted risk when no affected family members have been tested, and for at-risk relatives of known EPCAM variant carriers.>=5% predicted risk on validated models

EPCAM deletions can cause MSH2 silencing and are actionable.

JPS covered indications

JPS covered indications — individuals meeting clinical diagnostic criteria for juvenile polyposis syndrome or at-risk relatives

JPS_indications: Individuals meeting clinical diagnostic criteria for juvenile polyposis syndrome (≥5 juvenile polyps in the colon; multiple juvenile polyps elsewhere; or any juvenile polyps with family history) should undergo genetic testing for BMPR1A and SMAD4; at-risk relatives of affected individuals should be offered testing for known familial variants.

If a known SMAD4 variant exists in the family, testing may be performed early due to associated risks.

PJS covered indications

PJS covered indications — individuals meeting clinical diagnostic criteria for Peutz-Jeghers syndrome

PJS_indications: Individuals meeting clinical diagnostic criteria for Peutz-Jeghers syndrome (two or more histologically confirmed PJS polyps of the small intestine; characteristic mucocutaneous pigmentation; or family history of PJS) should undergo STK11 genetic testing and counseling for at-risk family members.

Testing of relatives for known familial STK11 variants is appropriate.

Use of somatic BRAF V600E or MLH1 methylation testing to exclude Lynch syndrome

Use of somatic BRAF V600E or MLH1 methylation testing to exclude Lynch syndrome when MLH1 protein is not expressed on IHC

BRAF_MLH1_triage: Perform somatic BRAF V600E or MLH1 promoter methylation testing in CRC tumors with absent MLH1 protein on IHC to help distinguish sporadic MLH1 loss from Lynch syndrome; positive somatic results can obviate germline MLH1 sequencing.

BRAF/methylation testing improves efficiency of Lynch evaluation and reduces unnecessary germline testing.

Probands testing and family cascade testing

Probands testing and family cascade testing — testing probands with CRC when clinical picture/family history suggests hereditary syndrome; family members tested for known familial pathogenic variants

Probands_and_cascade: Genetic testing of probands with CRC is indicated when clinical presentation or family history suggests FAP, attenuated FAP, MAP, or Lynch syndrome; tumor-screen-positive patients should proceed to germline MMR testing. Family members of probands with identified pathogenic variants should be offered targeted testing for the familial variant.

Whenever possible, initial testing should be performed in an affected family member to allow focused cascade testing.

Broad covered indications

Broad covered indications — suspected Lynch syndrome, FAP, MAP, JPS, PJS in affected individuals or at-risk relatives; tumor IHC/MSI patterns prompting reflex testing

Broad_indications: Testing is indicated to confirm diagnosis, guide surveillance or prophylactic treatment, and enable cascade testing of relatives for suspected Lynch syndrome, familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), juvenile polyposis syndrome (JPS), and Peutz-Jeghers syndrome (PJS) in affected individuals or at-risk relatives; tumor IHC/MSI patterns may prompt reflex somatic or germline testing.

Testing should follow guideline-based criteria (eg, NCCN, ASCO, EGAPP) and documented clinical indications.

Guideline-aligned testing

Guideline-aligned testing — testing guided by clinical criteria and professional guidelines (NCCN, ASCO, EGAPP)

Guideline_aligned: Testing for Lynch syndrome and other hereditary colorectal cancer syndromes should be guided by established clinical criteria and professional guidelines (eg, Amsterdam II, Revised Bethesda, NCCN, ASCO, EGAPP) and may incorporate validated risk models (PREMM, MMRpro, MMRpredict) to identify individuals with ≥5% predicted risk.>=5% predicted risk on validated models

Family history alone has limited sensitivity; population or tumor-based screening strategies are supported by guideline recommendations.

MSI-high on tumor screening indicates need for further evaluation for Lynch syndrome (eg, germline MMR testing)

Performance noteMSI and IHC have a 5%–10% false-negative rate; sensitivity varies by specific MMR gene variant

Predicted risk threshold — inv-28

Predicted-risk cutoff5% or higher predicted risk on a validated risk prediction model

Validated modelsExamples include MMRpro, PREMMs, and MMRpredict

ApplicationUsed to select individuals without affected family members for germline MMR testing

Refer to the member’s specific product benefit manual for applicability (e.g., FEP PPO refers to the FEP Medical Policy Manual)
Failure to follow product/program rules may affect coverage or reimbursement

Prior Authorization

Product-dependent prior authorization

Some products or programs may require prior authorization or have different benefit rules for genetic testing. Check the member’s plan and prior authorization requirements before ordering tests.

Confirm whether the specific Capital BlueCross product requires prior authorization for genetic testing
Obtain any required prior authorization prior to performing or submitting claims

Billing Rule

Code listing and medical necessity

Procedure and diagnosis codes included in this policy are examples of codes that may be used when services are medically necessary. Identification of a code in this section does not guarantee coverage; final coverage determination is based on the member’s benefit information and plan terms.

Code lists may not be all-inclusive and are subject to change
Coverage is contingent on the member’s benefit information

Billing Rule

Use current codes for authorization

Use current, effective procedure and diagnosis codes when requesting authorizations or submitting claims. Administrative coding changes (additions/removals) occur periodically; submitting outdated or removed codes may result in reimbursement issues or claim denials.

Providers must use current codes for authorization and billing
Be aware of recent code changes (see Policy History for dates of code updates)

Denial Risk

MUTYH testing investigational limits

Germline MUTYH testing is medically necessary only in specified circumstances (for example when differentiating MAP from attenuated FAP after a negative APC result or in appropriate clinical contexts). MUTYH testing is considered investigational for other indications not described in the policy.

Indicated: differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome after negative APC testing
Consider targeted testing for common MUTYH variants (Y165C, G382D) when appropriate; proceed to full sequencing based on ethnicity and clinical context
Investigational for indications outside those specified in the policy

Documentation Required

Coverage contingent on member benefits

Coverage of services described in this policy is determined by the member’s benefit plan. Even when a service is listed here as covered when medically necessary, the member’s specific benefits, limitations, exclusions, and prior authorization requirements control.

Verify member eligibility and specific benefit coverage before ordering testing
Not all covered services are eligible for separate reimbursement

Billing Rule

Coding change risk

Coding changes and administrative removals occur over time; providers should monitor policy history and code updates. Submission of outdated or removed codes may lead to denial or delayed payment.

Review the Policy History for recent coding updates and effective dates
Maintain current code sets in billing systems to reduce claim denials

Documentation Required

Testing sequencing and documentation

When possible, perform initial genetic testing in an affected family member so that testing in unaffected relatives can be limited to the known familial variant. If an affected relative is unavailable, begin testing with the unaffected family member most closely related to the affected individual.

Start familial testing in an affected member to identify a specific pathogenic variant for cascade testing
If no affected member is available, select the unaffected relative most closely related to the proband

Documentation Required

Required clinical documentation

Document clinical indications and counseling: pre-test genetic counseling, clinical indication for testing, relevant personal and family history, and informed consent should be included in the medical record. Documentation supports medical necessity determinations.

Document evidence of pre-test genetic counseling and discussion of implications
Include clinical indication, relevant cancer history, and pedigree/family history in the record
Record informed consent and test rationale

Documentation Required

Document clinical diagnostic criteria and family risk

For inherited polyposis and syndrome diagnoses (e.g., juvenile polyposis syndrome, Peutz-Jeghers syndrome), document that the patient meets established clinical diagnostic criteria or family risk thresholds prior to testing. Clinical criteria for JPS and PJS should be recorded when used to justify testing.

Document JPS diagnostic criteria (e.g., ≥5 juvenile polyps in the colon or relevant family history) when applicable
Document PJS diagnostic criteria (e.g., ≥2 histologically confirmed PJ polyps, characteristic mucocutaneous pigmentation, or family history)

Documentation Required

Tumor screening to guide germline testing

Tumor-based phenotype screening (MSI and/or IHC, with reflex BRAF or MLH1 methylation testing as applicable) is intended to guide subsequent germline testing decisions. Use the tumor screening strategy to prioritize gene sequencing and avoid unnecessary germline testing in cases likely to be sporadic.

IHC: absent staining for specific MMR proteins points to which gene(s) to sequence
MSI-high or abnormal IHC should prompt germline MMR testing according to results
Reflex BRAF V600E or MLH1 methylation testing can distinguish sporadic MLH1 loss from Lynch syndrome

Documentation Required

Counseling and family history documentation

Genetic counseling (pre- and post-test) and thorough family-history documentation are recommended and should be provided by clinicians with expertise in genetic medicine. Counseling may be considered medically necessary as an adjunct to testing and can influence appropriate test utilization.

Provide documented pre-test counseling prior to ordering genetic testing when feasible
Document uptake and result disclosure in the medical record; offer post-test counseling to interpret results and management implications

Note

Provider action (unspecified)

(No specific additional provider action specified in source chunks.)

When distinguishing between FAP, attenuated FAP, MAP, and Lynch syndrome, the policy supports a stepwise testing strategy—begin with the gene most consistent with the phenotype (often APC) and follow with MUTYH testing if APC is negative and clinical suspicion for MAP persists.

See the policy’s Summary of Evidence for detailed discussion of APC and MUTYH testing rationale: distinguishing FAP from MAP influences surveillance and management, and evidence supports genetic testing in probands and at-risk relatives when results will alter clinical care.

If APC testing is negative but clinical features suggest MAP, proceed to MUTYH testing. The policy reiterates this sequencing recommendation as part of the approach to differentiating polyposis syndromes; for full procedural details and documentation expectations, review the relevant policy sections.

Bethesda purposeRevised Bethesda guidelines broaden sensitivity to identify which CRC patients should have tumor MSI/IHC screening

Variant classification (ACMG-AMP) — inv-49

FrameworkACMG-AMP standardized terminology guides sequence variant interpretation

Outcome categoriesPathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, benign

Reporting guidanceApply ACMG-AMP criteria alongside laboratory standards when issuing clinical reports

MSI and IHC screening — inv-50

Tests definedMSI testing detects microsatellite instability; IHC assesses MMR protein expression (MLH1, MSH2, MSH6, PMS2)

InterpretationAbsent MMR protein on IHC or MSI-high indicates mismatch repair deficiency meriting further genetic evaluation

Screening roleTumor MSI and/or IHC are initial phenotype screens to guide germline MMR testing

LYNCH SYNDROME definition — inv-51

DefinitionLynch syndrome is a hereditary predisposition to nonpolyposis colorectal cancer and other solid tumors

Genes involvedTypically caused by pathogenic variants in MMR genes (eg, MLH1, MSH2, MSH6, PMS2) and EPCAM deletions affecting MSH2

Clinical relevanceIdentification alters surveillance and management for affected individuals and at-risk relatives

FAMILIAL ADENOMATOUS POLYPOSIS definition — inv-52

DefinitionFamilial Adenomatous Polyposis (FAP) is an inherited disorder characterized by development of numerous colonic polyps beginning in late adolescence/early adulthood

Natural historyIf untreated, FAP leads to colon cancer

Testing contextAPC gene testing is used to diagnose FAP and to inform management of at-risk relatives

EPCAM — inv-53

Gene roleEPCAM deletions can cause Lynch syndrome by leading to MSH2 inactivation

Testing indicationEPCAM testing considered when tumor shows loss of MSH2 expression or MSI-high and no MSH2 germline variant found

EvidenceLiterature documents recurrent EPCAM deletions associated with Lynch syndrome

BRAF V600E / MLH1 methylation — inv-54

RoleBRAF V600E mutation analysis or MLH1 promoter methylation testing are tumor markers used to help exclude Lynch syndrome in MSI-H colorectal cancers

ApplicationWhen MLH1 protein is not expressed on IHC, positive BRAF V600E or MLH1 methylation suggests sporadic CRC and may obviate germline MLH1 testing

Testing strategyBRAF testing can be used in conjunction with IHC; MLH1 methylation analysis may substitute for or complement BRAF testing

Removed CPT code 81436 from the policy, effective 01/01/2025.

2024-06-10administrative_update

Added procedure code 0474U to the policy (effective 07/01/2024).

2023-10-01administrative_update

Added diagnosis codes D1391 and D1399 to the policy.

2022-12-16consensus_review

Consensus review performed; no changes to the policy statement and no coding changes.

2021-12-15minor_review

Minor review updating juvenile polyposis syndrome (JPS) diagnostic criteria and MMR gene testing background; references updated.

2020-11-18administrative_update

Administrative update adding new procedure code 0238U to the policy.