OpenPayer is powered by Trek Health's payer performance platform. Trek continuously ingests, validates, and normalizes Transparency in Coverage data alongside payer policies and other commercial payer data to create a structured payer intelligence foundation. OpenPayer uses this foundation to deliver personalized search results, dynamically generated policy pages, and tailored policy monitoring based on each user's payers, specialties, billing codes, and areas of interest. The same intelligence powers broader payer performance workflows, including reimbursement benchmarking, contract evaluation, payer negotiations, and financial decision-making.

CurrentCapital BluecrossPolicy MP 5.013

Genetic testing for Lynch syndrome and other inherited colon cancer syndromes

Customize your policy alerts

Sign up for Capital Bluecross Policy MP 5.013 alerts

Get alerted when Policy MP 5.013 changes without checking for updates manually.

Monitor payer policy activity

Receive email alerts as soon as relevant payer policies are published or updated.

Defines medical necessity and investigational indications for germline and select somatic genetic tests related to Lynch syndrome, familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), and other inherited colon cancer syndromes for Capital Bluecross members and ordering clinicians.

Policy Summary

PayerCapital Bluecross

PolicyGenetic testing for Lynch syndrome and other inherited colon cancer syndromes

Policy CodePolicy MP 5.013

Change TypeAdministrative review — no material clinical changes

Effective DateJul 1, 2026

Last ReviewMar 4, 2026

Next Review Date

Key ActionPerform tumor-based MSI or IHC (± BRAF/methylation) before proceeding to targeted germline MMR gene sequencing and document results to support testing.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

multipleGene-specific rules

recommendedGenetic counseling

5%Risk model threshold

89%MSI sensitivity (MLH1/MSH2)

5-10%False-negative rate (MSI/IHC)

2020-2025Coding history

Coverage Criteria for Genetic Testing

inv-01: APC gene testing - Medically Necessary

Covered when ANY one of the following is met:

ANY of the following

At-risk relatives of known APC variant: At-risk relatives of individuals with familial adenomatous polyposis (FAP) and/or a known APC variant
See Policy Guidelines for at-risk relative definition
Differential diagnosis: Individuals with a differential diagnosis of attenuated FAP vs MUTYH-associated polyposis (MAP) vs Lynch syndrome; whether testing begins with APC variants or MMR depends on clinical presentation

APC investigational uses: Genetic testing for APC gene variants is investigational for colorectal cancer individuals with classical FAP for confirmation of the FAP diagnosis and investigational in all other situations not listed

Policy Summary

PayerCapital Bluecross

PolicyGenetic testing for Lynch syndrome and other inherited colon cancer syndromes

Policy CodePolicy MP 5.013

Change TypeAdministrative review — no material clinical changes

Effective DateJul 1, 2026

Last ReviewMar 4, 2026

Next Review Date

Key ActionPerform tumor-based MSI or IHC (± BRAF/methylation) before proceeding to targeted germline MMR gene sequencing and document results to support testing.

SourceLink

On This Page

inv-03: MMR gene testing (MLH1, MSH2, MSH6, PMS2) - Medically Necessary

Covered when ANY one of the following is met:

ANY of the following

CRC with tumor testing or clinical criteria: Individuals with colorectal cancer with tumor testing suggesting germline MMR deficiency or meeting clinical criteria for Lynch syndrome
See Policy Guidelines section
Endometrial cancer with tumor testing: 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 of known MMR variant: At-risk relatives of individuals with Lynch syndrome with a known pathogenic/likely pathogenic MMR gene variant
See Policy Guidelines
Unaffected individuals with family history or >=5% risk: Individuals without CRC but with a family history meeting the Amsterdam or Revised Bethesda criteria, or documentation of ≥5% predicted risk on a validated risk model when no affected family members have been tested for MMR variants≥5%
Models include MMRpro, PREMM5, MMRpredict

MMR investigational: Testing for germline MMR gene variants is investigational in all other situations

inv-04: EPCAM testing - Medically Necessary

Covered when ANY one of the following is met:

ANY of the following

CRC with loss of MSH2 and negative MSH2 germline: Individuals with CRC when tumor shows lack of MSH2 protein by IHC and patient is negative for a MSH2 germline variant
CRC with MSI-H and negative MMR germline: Tumor shows high microsatellite instability and patient is negative for germline variants in MSH2, MLH1, PMS2, and MSH6
At-risk relatives of EPCAM variant: At-risk relatives of patients with Lynch syndrome with a known EPCAM variant
Unaffected with family history and negative MMR sequencing: Individuals without CRC but meeting Amsterdam or Revised Bethesda criteria or ≥5% predicted risk when sequencing for MMR variants is negative≥5%

EPCAM investigational: Testing for germline EPCAM variants is investigational in other situations

inv-06: SMAD4 and BMPR1A testing - Medically Necessary

Covered when ANY one of the following major criteria is met:

ANY of the following

Clinical juvenile polyposis - >=5 colonic juvenile polyps: Individuals with a clinical diagnosis of juvenile polyposis syndrome based on at least five juvenile polyps in the colon
Clinical juvenile polyposis - multiple juvenile polyps extracolonic: Multiple juvenile juvenile polyps in other parts of the gastrointestinal tract
Any juvenile polyp with family history: Any number of juvenile polyps in a person with a known family history of juvenile polyps
At-risk relative of juvenile polyposis: At-risk relative of an individual suspected of or diagnosed with juvenile polyposis syndrome

SMAD4/BMPR1A investigational: Testing for SMAD4 and BMPR1A gene variants is investigational in all other situations

inv-10: Criteria for tumor screening and genetic testing referral

Tumor- and family-history-based clinical criteria (Amsterdam and Revised Bethesda) to identify individuals for tumor screening and further genetic evaluation:

Amsterdam criteria: Three or more relatives with an associated cancer (CRC, endometrium, small intestine, ureter, or renal pelvis); one should be a first-degree relative of the other two; two or more successive generations affected; one or more relatives diagnosed before age 50; familial adenomatous polyposis excluded; tumors verified by pathology. Modifications allow very small families to qualify with two CRCs in first-degree relatives if two generations affected and one diagnosed by age 55, or two first-degree relatives plus a third relative with early-onset neoplasm or endometrial cancer.

Revised Bethesda criteria: CRC diagnosed <50 years; synchronous or metachronous CRC or other HNPCC-associated tumors regardless of age; CRC with MSI-high histology <60 years; CRC in ≥1 first-degree relative with Lynch-associated tumor with one diagnosed <50; CRC in ≥2 first- or second-degree relatives with HNPCC-related tumors regardless of age.

Risk model threshold: Individuals with ≥5% predicted risk for Lynch syndrome on validated models (MMRpro, PREMM5, MMRpredict) are recommended for testing per NCCN (category 2A).>=5%

inv-12: APC/MUTYH testing criteria

Indications for APC and MUTYH testing:

APC testing indications: APC genetic testing may be considered for: patients with a family member with known APC pathogenic variant; patients in differential diagnosis of attenuated FAP vs MAP vs Lynch when clinical diagnostic criteria for classical FAP are not met and few adenomatous polyps are present; to confirm FAP in patients with colon cancer and compatible clinical picture or family history.

MUTYH considerations: When attenuated phenotype or 10–99 adenomas and APC testing is negative, consider MUTYH testing (biallelic MUTYH causes MAP); inheritance for MAP is autosomal recessive and biallelic variants confer high CRC risk.

Initial testing may target Y165C and G382D in white populations

inv-13: Indications for germline MMR and related genetic testing

Covered when ANY of the following indications are met:

Covered indications for MMR/germline testing: 1) Newly diagnosed CRC patients screened positive by MSI or IHC (with or without BRAF/methylation) warrant germline MMR testing; 2) Family members of Lynch syndrome patients with a known MMR pathogenic variant — targeted testing for the familial variant; 3) Patients with differential diagnosis including Lynch syndrome, attenuated FAP, or MAP; 4) Individuals with endometrial cancer and a first-degree relative with a Lynch-associated cancer; 5) Unaffected persons with family history meeting Amsterdam or Revised Bethesda criteria or with documentation of ≥5% predicted risk on validated model are candidates for testing.

Chain of evidence supports clinical utility for probands and at-risk relatives.

inv-16: Polyposis syndromes testing

Covered when clinical diagnostic criteria for polyposis syndromes are met:

JPS testing: Individuals meeting clinical criteria for juvenile polyposis syndrome (≥5 juvenile polyps in colon OR multiple juvenile polyps in other GI tract OR any juvenile polyps with family history) should undergo germline testing for BMPR1A and SMAD4; if a known SMAD4 familial variant exists, test within first 6 months of life.

Testing identifies at-risk relatives and can guide surveillance.

PJS testing: Individuals meeting clinical criteria for Peutz-Jeghers syndrome (≥2 histologically confirmed PJ polyps OR characteristic mucocutaneous pigmentation OR family history) should undergo STK11 germline testing.

STK11 variants detected in many families; testing confirms diagnosis and informs management.

Genetic testing for genes discussed in this policy (including APC, MUTYH, MLH1, MSH2, MSH6, PMS2, EPCAM, SMAD4, BMPR1A, and STK11) is considered investigational when performed in clinical situations other than the specific medically necessary indications enumerated in the policy. The policy lists gene- and syndrome-specific criteria under which testing may be considered medically necessary; testing performed outside those indications lacks sufficient evidence of clinical benefit and is therefore investigational.

Examples of investigational uses include routine sequencing of additional genes or panels not specified as covered indications, confirmation testing for classical FAP by APC sequencing when clinical criteria are already met, or germline testing for MMR genes when tumor- or family-history-based criteria are not satisfied. Refer to the gene-specific sections for the enumerated medically necessary indications and to the “Not Covered” language for common investigational scenarios.

Covered Indications and Populations

inv-77: APC gene testing for at-risk relatives of known APC variant or individuals in differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome.

APC testing for relatives and differential diagnosis: APC gene testing for at-risk relatives of known APC variant carriers or for individuals in the differential diagnosis of attenuated FAP versus MAP versus Lynch syndrome

See Policy Guidelines and testing strategy

inv-78: MUTYH testing for individuals in differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome with negative APC testing; initial testing may target common MUTYH variants in white populations (Y165C and G382D).

MUTYH testing after negative APC: MUTYH testing for individuals in the differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome when APC testing is negative; initial testing may target common MUTYH variants (Y165C and G382D) in white populations

MAP inheritance is typically autosomal recessive; family history without affected parents/children supports MAP

inv-79: MMR gene testing (MLH1, MSH2, MSH6, PMS2) for CRC or endometrial cancer with tumor testing suggesting germline MMR deficiency, at-risk relatives of known MMR variant carriers, or unaffected individuals meeting Amsterdam/Bethesda or ≥5% predicted risk.

MMR testing indications summary: MMR gene testing (MLH1, MSH2, MSH6, PMS2) is indicated for CRC or endometrial cancer with tumor testing suggesting germline MMR deficiency, at-risk relatives of known MMR variant carriers, unaffected individuals meeting Amsterdam or Revised Bethesda criteria, or individuals with ≥5% predicted risk on validated models; proceed to sequencing guided by MSI/IHC results, typically starting with MLH1 and MSH2 unless IHC directs otherwise.>=5%

Models include MMRpro, PREMM5, and MMRpredict

inv-80: EPCAM testing when specified tumor IHC/MSI criteria are met, for at-risk relatives of known EPCAM variant carriers, or in unaffected individuals with qualifying family history and negative MMR sequencing.

EPCAM testing summary: EPCAM testing is indicated when tumor IHC/MSI criteria are met (MSI-high and/or loss of MSH2) with negative MSH2 sequencing, for at-risk relatives of known EPCAM variant carriers, or for unaffected individuals with qualifying family history and negative MMR sequencing

EPCAM deletions (often last 2 exons) can silence MSH2 via promoter hypermethylation

inv-81: Somatic BRAF V600E or MLH1 promoter methylation testing to exclude Lynch syndrome when MLH1 protein is not expressed in CRC tumor on IHC.

Somatic triage to exclude Lynch: Somatic BRAF V600E or MLH1 promoter methylation testing is appropriate to exclude Lynch syndrome when MLH1 protein is not expressed on CRC tumor IHC; presence of BRAF V600E or MLH1 methylation suggests sporadic CRC and may obviate germline MLH1 sequencing

BRAF-positive samples need not be further tested by MLH1 sequencing

inv-82: SMAD4 and BMPR1A testing for clinical juvenile polyposis syndrome defined by specified polyp criteria or at-risk relatives.

JPS testing indications: SMAD4 and BMPR1A testing for individuals with clinical juvenile polyposis syndrome (≥5 juvenile colonic polyps, multiple juvenile polyps elsewhere in GI tract, or any juvenile polyps with family history) and for at-risk relatives

If a known SMAD4 familial variant exists, test within first 6 months of life due to HHT risk

inv-83: STK11 testing for clinical Peutz-Jeghers syndrome meeting clinical criteria or at-risk relatives.

PJS testing indications: STK11 testing for individuals meeting clinical criteria for Peutz-Jeghers syndrome (any two of ≥2 histologically confirmed PJ polyps, characteristic mucocutaneous pigmentation, or family history) and for at-risk relatives

inv-84: Clinical qualification summary — Individuals meeting Amsterdam criteria, Revised Bethesda criteria, or with ≥5% risk on validated risk models; patients with tumor screening results (MSI-high or absent MMR proteins) indicating probable MMR deficiency; patients with family or clinical features suggesting FAP or attenuated FAP/MAP as described.

Clinical qualification summary: Individuals meeting Amsterdam or Revised Bethesda criteria, or with ≥5% predicted risk on validated models; patients with tumor screening results (MSI-high or absent MMR proteins) indicating probable MMR deficiency; patients with family or clinical features suggesting FAP, attenuated FAP, or MAP as described are candidates for tumor screening and/or germline testing>=5%

Risk models include MMRpro, PREMM5, MMRpredict; NCCN recommends ≥5% threshold (category 2A)

inv-85: Typical covered scenarios — Newly diagnosed CRC with positive tumor screening (MSI or IHC), probands with suspected Lynch/FAP/MAP, at-risk relatives of known variant carriers, endometrial cancer with first-degree relative with Lynch-associated cancer, and individuals meeting Amsterdam or Revised Bethesda criteria or ≥5% risk on validated model.

Typical covered scenarios: Newly diagnosed CRC with positive tumor screening (MSI or IHC), probands with suspected Lynch/FAP/MAP, at-risk relatives of known variant carriers, endometrial cancer with first-degree relative with Lynch-associated cancer, and individuals meeting Amsterdam or Revised Bethesda criteria or ≥5% risk on validated model

Tumor-based screening (MSI/IHC ± BRAF/methylation) guides germline testing

inv-86: JPS/PJS criteria — Individuals meeting clinical criteria for JPS or PJS and at-risk relatives for BMPR1A, SMAD4, or STK11 testing.

JPS/PJS criteria summary: Individuals meeting clinical criteria for juvenile polyposis syndrome or Peutz-Jeghers syndrome and at-risk relatives should be considered for BMPR1A/SMAD4 or STK11 testing respectively

Clinical diagnostic criteria described in policy

inv-87: Relevant diagnosis codes context — Colorectal malignancy, carcinoma in situ, benign neoplasms, personal or family history of colorectal neoplasia or polyposis (ICD codes listed).

Relevant diagnosis codes context: Relevant ICD-10 diagnosis codes include colorectal malignancy, carcinoma in situ, benign neoplasms, personal or family history of colorectal neoplasia or polyposis; documentation of these codes may support testing indications

See coding section for specific codes

inv-88: References for covered indications — References and guidelines for hereditary colorectal cancer risk assessment and surveillance (e.g., Lynch syndrome) are cited.

References for covered indications: Guidelines and references (e.g., NCCN, PREMM models, systematic reviews) are cited to support indications for hereditary colorectal cancer risk assessment and surveillance

See References section

Eligibility Requirements and Testing Preconditions

For the purposes of eligibility and family-based testing, at‑risk relatives are primarily considered to be first‑degree relatives (parents, siblings, children). Extended family can be included when constructing small pedigrees.

Family history examples that may support testing include patterns such as at least two second‑degree relatives with a Lynch‑related cancer (for example, grandparent, aunt/uncle, niece/nephew) or other family constellations meeting Amsterdam or Revised Bethesda criteria. Documentation of multigenerational affected relatives and ages at diagnosis informs eligibility.

Testing eligibility emphasizes first‑degree relatives as the primary at‑risk group, but clinical judgment may extend consideration to second‑degree relatives when family size is small or when multiple affected second‑degree relatives are present. A family history that includes at least two affected second‑degree relatives with Lynch‑related cancers may support further evaluation.

When a known familial pathogenic variant is identified, unaffected relatives should be offered targeted testing for that specific familial variant rather than broad initial panel testing.

Eligibility for germline testing often relies on documented family history; first‑degree relatives of an affected individual with a known pathogenic variant are primary candidates for targeted testing. In smaller pedigrees, individuals with two or more affected second‑degree relatives may also meet criteria for testing.

Where possible, testing should begin in an affected family member (the proband) to identify a familial pathogenic variant that can then be tested for in at‑risk relatives.

At‑risk relative definitions focus on first‑degree relatives but acknowledge that extended family members can be included in pedigree assessment; a history of two or more second‑degree relatives with Lynch‑related cancer can be supportive evidence for pursuing genetic evaluation.

Clinical documentation should include verification of cancers in relatives (pathology or medical records) and ages at diagnosis to determine whether Amsterdam or Revised Bethesda criteria are met.

First‑degree relatives are prioritized as at‑risk individuals for targeted testing. When family history is limited, the presence of multiple affected second‑degree relatives (for example, two or more) may be used to justify further genetic evaluation for Lynch syndrome.

Testing of unaffected relatives is generally targeted to a known familial pathogenic variant; broad germline panel testing in unaffected relatives is appropriate only when no familial variant has been identified and coverage criteria are otherwise met.

Eligibility considerations emphasize that at‑risk relatives are typically first‑degree relatives, with the possibility of including second‑degree relatives in pedigrees demonstrating multiple Lynch‑related cancers. Such family history patterns help determine candidacy for tumor screening and germline testing.

Providers should record the relationship, diagnosis, and age at diagnosis for affected relatives to support eligibility determinations and any necessary prior authorization.

Primary eligibility for testing is based on first‑degree relative status; however, a family history that contains at least two second‑degree relatives with Lynch‑related cancers can be sufficient to warrant further genetic evaluation in certain clinical contexts.

Documentation of family history and verification of tumors (pathology reports) are recommended to substantiate testing eligibility under the policy.

For MUTYH testing specifically, when an individual is of Northern European or white ancestry, initial testing may target the two common variants Y165C and G382D prior to proceeding to full gene sequencing. In individuals from other ethnic backgrounds or when targeted testing is not informative, full MUTYH sequencing and deletion/duplication analysis may be appropriate.

This targeted‑first approach reflects the higher prevalence of these founder variants in certain populations and can be a pragmatic, stepwise strategy to identify biallelic MUTYH carriers in the differential diagnosis of attenuated FAP versus MAP.

The policy allows for population‑tailored MUTYH testing: begin with targeted analysis for Y165C and G382D in white populations where these variants are common; if targeted testing is negative or the individual’s ancestry suggests other variant distributions, proceed to comprehensive sequencing.

When clinical suspicion for MAP remains after negative targeted testing, full gene sequencing and deletion/duplication analysis should be considered to identify biallelic pathogenic variants.

When ordering MUTYH testing, document the patient’s ancestry and prior APC testing results. If APC sequencing is negative and the phenotype suggests MAP, targeted MUTYH testing for Y165C and G382D may be an appropriate initial step in white populations; otherwise, proceed to comprehensive testing.

Testing plans should be recorded in the medical record to support the chosen strategy and any necessary benefit or prior‑authorization reviews.

MUTYH testing strategy emphasizes efficiency by recommending targeted testing for the Y165C and G382D variants first in populations where these are prevalent, and full sequencing in other ethnic groups or when targeted results are negative and clinical suspicion persists.

These recommendations align with the policy’s differential‑diagnosis approach for individuals with attenuated polyposis phenotypes after APC testing is negative.

Provider Actions and Documentation Requirements

Documentation Required

Genetic counseling — offer pre- and post-test counseling and document encounters

Offer pre- and post-test genetic counseling as an adjunct to genetic testing; counseling by individuals experienced in genetic medicine is recommended and documentation of counseling encounters is relevant.

Pre- and post-test counseling may be considered medically necessary.
Document encounters (e.g., ICD-10 Z31.5) when counseling is provided.

Prior Authorization

Product-dependent prior authorization — verify member product/benefit and prior auth needs

Check the member's specific product and benefit program before ordering tests; certain products are subject to benefit variations and may require prior authorization.

This policy applies only to certain Capital Blue Cross programs and products and is subject to benefit variations.
Payment and coverage depend on the member's benefit program and eligibility on the date of service.

Billing Rule

Lab regulatory requirement — use CLIA high-complexity certified laboratories

Use laboratories that meet CLIA high-complexity requirements for genetic testing; laboratory-developed tests must be performed in CLIA-certified high-complexity labs.

Clinical laboratories must meet Clinical Laboratory Improvement Amendments standards for high-complexity testing.
The FDA has not required regulatory review of these tests; CLIA licensing is required.

Prior Authorization

Prior authorization depends on member benefit and coding — verify coverage and codes

Prior authorization requirements may depend on member benefits and coding; presence of a code in the coding section does not guarantee coverage and prior auth may be required per member benefit information.

The list of codes may not be all-inclusive and identification of a code does not denote coverage.
Final claim payment is subject to member benefit terms and medical necessity determinations.

Prior Authorization

Prior authorization may be delegated — follow EviCore or delegated vendor procedures

Prior authorization and utilization management for these genetic tests may be administered by a delegated vendor (EviCore) per the policy retirement review; providers should follow delegated-review processes when applicable.

Retirement review notes EviCore delegation for utilization management.
Follow the delegated vendor's authorization process when indicated.

Step Therapy

Tumor-first evaluation — use tumor MSI/IHC (± BRAF/methylation) to guide germline testing

Perform MSI or IHC (with reflex BRAF/methylation testing when indicated) on tumor tissue before proceeding to germline MMR sequencing; use tumor results to guide which MMR genes to sequence.

IHC may direct which MMR gene likely contains a variant; begin sequencing with MLH1 and MSH2 unless IHC directs otherwise.
Standard sequencing may miss large deletions/duplications—consider additional testing when indicated.

Step Therapy

Stepwise testing approach — tumor screening then targeted germline sequencing; consider EPCAM when MSH2 sequencing is negative

Follow the testing pathway: tumor screening with MSI or IHC (± BRAF/methylation) followed by targeted germline sequencing of MLH1/MSH2 and, if negative, MSH6/PMS2; perform EPCAM testing when tumor suggests MSH2 deficiency but MSH2 sequencing is negative.

If tumor shows loss of MSH2 by IHC and MSH2 germline testing is negative, test for EPCAM deletions.
If MLH1 IHC loss is explained by BRAF V600E or MLH1 promoter methylation, further germline MLH1 sequencing may be unnecessary.

Documentation Required

Familial testing documentation — test an affected family member first when possible

When possible, perform initial testing in an affected family member so that testing of unaffected relatives can be limited to the identified familial variant; if no affected relative is available, test the unaffected relative most closely related to an affected member.

Targeted familial variant testing reduces unnecessary broad testing in unaffected relatives.
For MUTYH in white populations, consider initial targeted testing for Y165C and G382D before broader sequencing.

Documentation Required

Tumor testing documentation — record MSI/IHC and BRAF/methylation results when MLH1 absent

Document tumor testing (MSI or IHC) results, including BRAF V600E or MLH1 promoter methylation when MLH1 is absent, as part of the evaluation for Lynch syndrome prior to germline MMR analysis.

Tumor phenotype results should be used to justify and direct subsequent germline testing.
Record tumor pathology verification as recommended by Amsterdam/Bethesda criteria.

Documentation Required

Family history and tumor verification — document Amsterdam/Bethesda criteria or risk-model results

Document family history consistent with Amsterdam or Revised Bethesda criteria (or risk-prediction model results ≥5%) and verify tumor pathology to support eligibility for tumor screening and germline testing.

Use Amsterdam II or Revised Bethesda criteria to document high-risk family history.
A ≥5% predicted risk on validated models (MMRpro, PREMM5, MMRpredict) supports testing when no affected family members have been tested.

Documentation Required

Document tumor screening, family history, and risk-model results to support testing

Include tumor screening results (MSI and/or IHC), family history or risk-prediction model outputs (e.g., Amsterdam/Bethesda criteria or ≥5% predicted risk), and BRAF/methylation results (when applicable) in the medical record to justify germline testing.

Documenting these elements supports medical necessity determinations for germline MMR testing.
Ensure tumor-based triage testing results are clearly recorded when used to avoid unnecessary germline sequencing.

Documentation Required

Document genetic counseling encounters (Z31.5) when counseling is provided

When genetic counseling is provided, consider documenting the encounter (Z31.5) as part of the record; this diagnosis code is listed among relevant codes and indicates counseling encounters are relevant to testing.

Use Z31.5 to document an encounter for genetic counseling when applicable.
Counseling documentation may affect utilization and appropriateness of testing.

Billing Rule

Coding documentation impact — use current effective codes and monitor policy updates

Monitor policy coding updates and use current effective procedure and diagnosis codes when submitting claims; administrative code changes recorded in policy history may affect claim adjudication.

Code additions/removals in policy history (e.g., 0238U, 0474U, removal of 81436) illustrate the need to use current codes.
Identification of a code in the policy does not guarantee coverage—verify member benefits.

Denial Risk

APC testing investigational use — avoid germline APC testing to confirm classical FAP

Do not order germline APC testing for confirmation of classical FAP solely for diagnostic confirmation in classical FAP cases; germline APC testing for confirmation of classical FAP is considered investigational and not supported as medically necessary.

APC testing is appropriate for at-risk relatives of known APC variant carriers or in differential diagnosis scenarios, but not for confirming classical FAP.
Testing outside listed indications is considered investigational.

Denial Risk

MUTYH testing investigational uses — limit testing to listed differential-diagnosis indications

Avoid ordering germline MUTYH testing in situations outside the specified indications; MUTYH testing is considered investigational except when used for differential diagnosis after negative APC testing per the policy criteria.

MUTYH testing is medically necessary only when APC testing is negative in the differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome.
Testing for MUTYH outside these indications may be denied as investigational.

Denial Risk

MMR testing investigational uses — order only when coverage criteria are satisfied

Order germline MMR gene testing only when the listed coverage criteria are met (tumor screening suggestive of germline MMR deficiency, qualifying cancer family history, at-risk relatives of known carriers, or ≥5% predicted risk); germline MMR testing is investigational in other situations.

Indications include CRC or endometrial cancer with tumor testing suggesting MMR deficiency, at-risk relatives of known MMR variant carriers, and unaffected individuals meeting Amsterdam/Bethesda or ≥5% risk criteria.
Testing outside these criteria may be considered investigational and denied.

Denial Risk

EPCAM testing investigational uses — restrict EPCAM testing to specified criteria

Do not order EPCAM germline testing except in the enumerated situations (e.g., MSH2 IHC loss with negative MSH2 sequencing, at-risk relatives of known EPCAM carriers, or qualifying family history with negative MMR sequencing); EPCAM testing is investigational outside those criteria.

EPCAM testing is indicated when tumor is MSI-high and/or shows MSH2 loss and MSH2 sequencing is negative.
Ordering EPCAM testing outside policy indications risks denial as investigational.

Prior Authorization

Product variation applicability — verify coverage under the member's specific product

Confirm that the requested test is covered under the member's specific Capital Blue Cross product before ordering; tests inconsistent with product benefit variations may be denied.

This policy applies only to certain Capital Blue Cross programs and products and is subject to benefit variations.
Verify coverage and prior-authorization requirements per the member's product.

Denial Risk

MLH1 IHC loss documentation gap risk — perform and document BRAF/methylation testing when MLH1 absent

If MLH1 protein is absent on IHC, ensure BRAF V600E testing or MLH1 promoter methylation testing is performed and documented; failure to do so may lead to unnecessary germline MLH1 testing and potential denial.

BRAF V600E or MLH1 promoter methylation consistent with sporadic CRC can obviate further germline MLH1 sequencing.
Document tumor triage testing results in the medical record to support decision-making and authorization.

Denial Risk

Coverage determination dependencies — ensure medical necessity and member eligibility

Recognize that coverage determinations require a finding of medical necessity and member eligibility on the date of service; absence of documentation supporting medical necessity or ineligibility may result in denial.

Final claim processing depends on member benefit contract terms and medical necessity determinations.
Providers are responsible for ensuring services are medically necessary and documented.

Denial Risk

Coding changes may trigger denial risk — use current active codes when billing

Administrative and coding edits reflected in the policy history (code additions/removals) may affect claim adjudication; ensure billing uses currently active codes to avoid claim denials.

Policy history documents additions (e.g., 0238U, 0474U) and removals (e.g., 81436) of codes over time.
Use current effective procedure and diagnosis codes when submitting claims.

Prior Authorization

Delegated review/authorization — follow EviCore or delegated vendor authorization process

When prior authorization is required, the delegated vendor (EviCore) may handle utilization management and authorization; follow delegated review instructions where applicable.

Retirement review records EviCore delegation for prior authorization/utilization management.
Contact the delegated vendor for authorization procedures when indicated.

Coding and Diagnosis Codes

Covered CPT/PLA codes (partial list)CPTCovered

0157U
0158U
0159U
0160U
0161U
0162U
0238U
0474U
81201

Covered molecular CPT codes (continued, partial)CPTCovered

81202
81203
81210
81288
81292
81293
81294
81295
81296
81297

1–10 of 19

1/2

Relevant ICD-10 diagnosis codesICD-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 / overlapping sites
C18.8	Malignant neoplasm of overlapping sites of colon
C18.9	Malignant neoplasm of colon, unspecified

1–10 of 35

1/4

Policy history coding changesmixed

0238U	Added new code 0238U (policy history entry)
0474U	Added code 0474U effective 07/01/2024 (policy history entry)
81436	Removed 81436 effective 01/01/2025 (policy history entry)
0421U	Removed code 0421U (policy history entry)
D1391	Added diagnosis code D1391 (policy history entry)
D1399	Added diagnosis code D1399 (policy history entry)
Z15.060	Added ICD-10 code Z15.060 effective 10/01/2025 (policy history entry)

Predicted risk threshold — inv-30

Predicted risk threshold≥ 5% predicted risk on a validated risk model (e.g., MMRpro, PREMM5, MMRpredict) when no affected family members have been tested

Context for useApplies to unaffected individuals without CRC when family history meets Amsterdam/Bethesda criteria or risk model result is documented

Models referencedExamples: MMRpro, PREMM5, MMRpredict

Risk prediction model threshold — inv-31

Risk prediction model threshold>= 5% predicted risk on MMRpro, PREMM5, or MMRpredict

Guideline basisThreshold recommended by NCCN (category 2A) for Lynch syndrome testing

Intended populationIndividuals without CRC when no affected family members have been tested

MSI positivity criteria — inv-32

MSI-high definitionMSI detected in 2 of 5 Bethesda markers = MSI-high

Testing methodNational Cancer Institute panel of 5 markers recommended for MSI detection

Clinical implicationMSI-high is considered positive screening for possible Lynch syndrome and prompts further evaluation

PREMM5 risk model reference — inv-33

PREMM5 referenceSee PREMM5 (PREMM(1,2,6)/PREMM5) risk model for predicting MLH1/MSH2/MSH6 mutation risk

Key citationKastrinos et al., PREMM(1,2,6) model (Gastroenterology 2011) referenced in policy

Use caseUsed alongside MMRpro and MMRpredict as validated risk models to guide testing thresholds

Provisions and Exclusions — Not Covered / Investigational

Genetic testing for gene variants beyond those specifically addressed in the policy (APC, MUTYH, MLH1, MSH2, MSH6, PMS2, EPCAM, SMAD4, BMPR1A, STK11) is considered not covered / investigational. The policy states there is insufficient evidence to support routine clinical use of testing for other genes associated with Lynch syndrome or hereditary colorectal cancer.

Providers should not assume that additional genes or broader panels outside the policy’s covered indications are eligible for coverage; benefit determination remains subject to the member’s plan provisions.

Germline MLH1 sequencing is generally not required when tumor MLH1 protein loss is explainable by a somatic BRAF V600E mutation or by MLH1 promoter methylation, since these somatic findings are strongly associated with sporadic colorectal cancer rather than Lynch syndrome.

When BRAF V600E or MLH1 promoter methylation is present in the tumor, further germline MLH1 analysis and Lynch syndrome–directed germline testing are typically unnecessary because the tumor phenotype is most consistent with a sporadic etiology.

Routine clinical testing for germline epivariants (for example, germline promoter methylation testing as a primary diagnostic approach) is not performed as standard practice and is considered appropriate only in exceptional, well‑justified cases. The policy notes that germline epivariants are rare and clinical testing is not routine.

Such specialized testing should be considered on a case‑by‑case basis and typically only after standard germline and somatic testing strategies have been exhausted and documented.

The coding section of the policy includes procedure and CPT/PLA codes for informational purposes, but the presence of a code does not imply coverage. Coverage is determined by the member’s benefit plan and applicable coverage rules; some listed services may not be separately reimbursable.

Providers should verify coverage and billing eligibility with the payer and follow any required prior authorization or benefit‑specific processes.

This excerpt does not list specific tests or clinical indications that are explicitly excluded beyond the investigational not‑covered statements; policy history notes administrative edits and coding updates but no additional explicit exclusions are present in the provided excerpt.

For services not addressed in this excerpt, providers should consult the complete policy text and the member’s benefits to determine coverage status.

Background and Rationale

This policy addresses germline genetic testing for inherited colorectal cancer syndromes including familial adenomatous polyposis (FAP) (APC), MUTYH‑associated polyposis (MAP) (MUTYH), and Lynch syndrome (MMR genes MLH1, MSH2, MSH6, PMS2 and EPCAM), as well as testing for genes associated with juvenile polyposis (SMAD4, BMPR1A) and Peutz‑Jeghers syndrome (STK11).

It also includes somatic tumor testing used for Lynch triage—specifically BRAF V600E mutation analysis and MLH1 promoter methylation testing—to help distinguish sporadic colorectal cancers from those due to Lynch syndrome and to guide whether germline MLH1 testing is indicated.

Lynch syndrome gene references — inv-75

Primary Lynch genes referencedEvidence and references include germline mutations in MLH1, MSH2, MSH6 (and PMS2) associated with Lynch syndrome

Additional genes notedReferences also discuss other implicated genes and large-deletion analyses relevant to hereditary colorectal cancer

Supporting literatureMultiple citations provided (e.g., Bonadona et al., Quehenberger et al.) documenting cancer risks for MLH1/MSH2/MSH6 carriers

NCCN guideline references — inv-76

NCCN guidelines citedNCCN Clinical Practice Guidelines: Genetic/Familial High-Risk Assessment: Colorectal (Version 3.2024) and Colorectal Cancer Screening (Version 1.2024)

Role of guidelinesNCCN guidance supports use of validated risk models and testing thresholds (e.g., >=5% predicted risk) cited in policy

Definitions and Key Terms

At-risk relatives — inv-60

Primary at-risk relativesPrimarily first-degree relatives (parent, offspring, siblings)

Extended family inclusionIn small pedigrees, extended family members may be included in testing strategies

Example family-history patternsExamples: at least two second-degree relatives with Lynch-related cancer including one diagnosed before age 50, or at least three second-degree relatives regardless of age

Targeted familial variant testing — inv-61

Preferred testing sequenceWhen possible, test an affected family member first and then perform targeted testing in unaffected relatives for the specific familial variant

MUTYH specificsFor MUTYH, initial testing may target common variants Y165C and G382D in white populations before sequencing

If affected member unavailableBegin testing with the unaffected relative most closely related to an affected family member

Variant classification — inv-62

ACMG-AMP variant classificationRecommended terminology: pathogenic, likely pathogenic, uncertain significance, likely benign, benign

Standards referencedACMG-AMP standards and guidelines and Table PG2 summarized in policy

Reporting implicationsThese terms are used for clinical reporting of sequence variants in DNA testing

Microsatellite instability (MSI) — inv-63

MSI definitionMSI is a tumor phenotype from deficient mismatch repair leading to instability at microsatellite loci; MSI-high indicates probable MMR deficiency

Clinical roleMSI-high tumors (~80–90% of Lynch CRC tumors) prompt further germline MMR evaluation

LimitationsSome MSH6-associated tumors may show MSI-low; MSI-low should not be used to withhold testing when suspicion exists

Immunohistochemistry (IHC) for MMR proteins — inv-64

IHC targetsIHC stains tumor tissue for MLH1, MSH2, MSH6, and PMS2 proteins

InterpretationAbsence of protein expression suggests dysfunction of the corresponding MMR gene and guides which gene(s) to sequence

Clinical pathwayLoss of MLH1 on IHC should prompt BRAF V600E and/or MLH1 promoter methylation testing to triage germline MLH1 sequencing

MSI — inv-65

MSI testing roleMicrosatellite instability testing used as tumor-screening method for mismatch repair deficiency with variable sensitivity across MMR genes

Sensitivity notesMSI sensitivity varies by gene (policy notes ~80–90% of Lynch CRC tumors show MSI)

Screening implicationMSI-high results are used to select patients for germline MMR testing

BRAF V600E — inv-66

BRAF V600E descriptionBRAF V600E is an activating somatic variant (valine to glutamic acid at codon 600); its presence in CRC is associated with sporadic MLH1 promoter methylation

Triage implicationBRAF V600E positive tumors with MLH1 loss on IHC are likely sporadic and usually do not require MLH1 germline sequencing

Metachronous — inv-67

Metachronous definitionMetachronous: not synchronous; multiple separate occurrences developing at intervals

Clinical usageTerm used in Revised Bethesda/Ams criteria descriptions for multiple primary tumors

Mutation — inv-68

Mutation definitionMutation: an unusual change in genetic material occurring spontaneously or by induction

ContextGeneral genetics glossary term used in policy definitions

Noninvasive — inv-69

Noninvasive definitionNoninvasive: a device or procedure that does not penetrate the skin or enter any orifice in the body

RelevancePolicy glossary term; not specific to genomic testing procedures

Phenotype — inv-70

Phenotype definitionPhenotype: the expression of genes present in an individual, observable or apparent only with tests

Policy relevanceUsed to describe tumor phenotypes such as MSI

Polyposis — inv-71

Polyposis definitionPolyposis: presence of numerous polyps

Clinical relevanceUsed in criteria for FAP, JPS, and PJS testing indications

Second degree relative — inv-72

Second-degree relative definitionSecond-degree relative: grandparent, grandchild, uncle, aunt, nephew, niece, half-sibling

ContextUsed in family-history examples for at-risk relative definitions

Synchronous — inv-73

Synchronous definitionSynchronous: occurring at the same time

Clinical useUsed in Revised Bethesda criteria (synchronous/metachronous tumors)

Screening — inv-74

Screening definitionScreening: evaluating a patient for diseases before they become clinically obvious

Policy applicationApplies to tumor screening tests (MSI/IHC) used to triage germline testing

Policy Revision History

2026-03-04retirement_review

Retirement review noting EviCore delegation for prior authorization and administrative updates to disclaimer

2025-10-01coding_update

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 and removal of code 0421U; no change in policy intent

2024-12-13administrative_update

Removed prior NCCN statement from the policy (administrative update)

2024-12-10administrative_update

Removed CPT code 81436 effective 01/01/2025

2024-08-19administrative_update

Added ICD-10 codes effective 10/01/2024

2024-06-10administrative_update

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

2023-10-01administrative_update

Added new diagnosis codes D1391 and D1399 to the policy

2022-12-16consensus_review

Consensus review with no changes to the policy statement; background and references updated

2021-12-15minor_review

Minor review updating JPS diagnosis criteria and MMR gene testing; background and references updated and coding reviewed

2020-11-18administrative_updateLatest

Added new code 0238U to the policy

Note