CurrentCapital BluecrossPolicy MP 5.013

Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes

Defines medical necessity criteria for germline and select somatic genetic tests (APC, MUTYH, MMR genes MLH1/MSH2/MSH6/PMS2, EPCAM, BRAF V600E, MLH1 promoter methylation, SMAD4, BMPR1A, STK11) and genetic counseling, including at-risk relative testing and tumor-screening strategies to guide germline testing.

Policy Summary

PayerCapital Bluecross

PolicyGenetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes

Policy CodePolicy MP 5.013

Change TypeAdministrative code and content updates

Effective Date12/1/2025

Next Review Date

Key ActionProviders should document MSI or IHC tumor testing results (and BRAF/methylation if performed), clinical criteria met (Amsterdam II or Revised Bethesda), and family history including at-risk relatives to support medical necessity for germline testing

SourceLink

POLICY UPDATE CHANGES

Added code 0238U.

Added code 0474U.

Added ICD-10 code Z15.060.

Removed code 81436.

Removed code 0421U.

Added new diagnosis codes D1391 and D1399 to the policy.

Removed NCCN statement.

Removed Benefit Variations Section and updated Disclaimer.

MP 5.013Policy ID

>=5%Risk model threshold for testing

Estimated proportion of CRC due to Lynch syndrome

~30Listed ICD-10 and molecular/procedure codes

MultipleReferences cited

Coverage Summary

Hereditary colorectal cancer syndromes include familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), Lynch syndrome, juvenile polyposis syndrome (JPS), and Peutz-Jeghers syndrome (PJS). Tumor-based screening strategies such as microsatellite instability (MSI) testing and immunohistochemistry (IHC) for mismatch repair (MMR) proteins are used to identify tumors suggestive of an underlying germline MMR defect and to guide subsequent germline genetic testing. IHC can direct which MMR gene to test and MSI/IHC help prioritize sequencing; when IHC shows loss of MLH1, somatic BRAF V600E or MLH1 promoter methylation testing can exclude sporadic cases and obviate MLH1 germline sequencing. Targeted familial variant testing is recommended when a pathogenic variant is known in an affected family member so unaffected relatives can be tested for the specific familial variant. Gene-specific indications exist (e.g., APC for FAP, MUTYH for MAP, MMR genes and EPCAM for Lynch, SMAD4/BMPR1A for JPS, STK11 for PJS) because each syndrome has distinct inheritance patterns, risks, and management implications.

Scope summary: This policy defines medical necessity criteria for germline and select somatic genetic tests — including APC, MUTYH, MMR genes (MLH1, MSH2, MSH6, PMS2), EPCAM, BRAF V600E, MLH1 promoter methylation, SMAD4, BMPR1A, and STK11 — and for genetic counseling, addressing at-risk relative testing and tumor-screening strategies to guide germline testing.

High-level thresholds & quick facts

Risk model threshold for testing>=5%

Estimated proportion of CRC due to Lynch syndrome3-5%

Policy IDMP 5.013

Listed ICD-10 and molecular/procedure codes~30 codes listed (examples include CPT/proprietary: 0157U-0162U, 0238U, 0474U; molecular: 81201-81319, 81403, 81435; ICD-10: C18.0–C18.9, C19, C20, D01.x, D12.x, D13.91, Z15.060, Z31.5, Z80.0, Z83.72, Z86.010x)

Medical-Necessity Criteria

APC Testing - Medically Necessary

Genetic testing for APC gene variants may be considered medically necessary when any one of the following is met. Note: At-risk relatives primarily refers to first-degree relatives (see Policy Guidelines).

Any of the following: At-risk relatives of individuals with familial adenomatous polyposis (FAP) and/or a known APC pathogenic/likely pathogenic variant.

Individuals with a differential diagnosis of attenuated FAP vs MUTYH-associated polyposis (MAP) vs Lynch syndrome — clinical presentation should guide whether APC testing or MMR testing is performed first.

Policy guidance: Genetic testing for APC in individuals with classical FAP for confirmation of the FAP diagnosis is considered investigational. APC testing is investigational in all other situations not listed above.

APC Testing - Not Medically Necessary / Investigational

Genetic testing for APC gene variants is not medically necessary / investigational when ALL of the following apply.

Coding

Covered when medically necessary - Procedure / CPT / Proprietary codes listedmixedCovered

0157U
0158U
0159U
0160U
0161U
0162U
0238U
0474U
81201
81202

1–10 of 11

1/2

Covered when medically necessary - Procedure / Molecular CodesCPT|HCPCS|mixedCovered

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 (added per policy history 11/18/2020)
0474U	Procedure code listed as covered when medically necessary (added per policy history 06/10/2024; effective 07/01/2024)
81201	Molecular diagnostic code listed as covered when medically necessary
81202	Molecular diagnostic code listed

1–10 of 28

1/3

Relevant ICD-10 Diagnosis Codes (policy lists as applicable)ICD-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
C18.8	Malignant neoplasm of overlapping sites of colon
C18.9	Malignant neoplasm of colon, unspecified

1–10 of 47

1/5

Removed / Historical Codes (per policy history)CPT|HCPCS|mixedNot Covered

81436	Removed effective 01/01/2025 (per policy history)
0421U	Removed (per policy history entry 01/13/2025)

Codes listed in the policy are identified as 'Covered when medically necessary' or as relevant diagnosis codes, but the identification of a code in the policy does not by itself guarantee coverage. Coverage determination depends on the member's specific benefit information and a finding of medical necessity. Providers should verify benefit eligibility and follow any prior-authorization or documentation requirements.

Provider Actions

Documentation Required

Document tumor screening results and family history

Document MSI or IHC tumor testing results (and BRAF or MLH1 methylation if performed), the clinical criteria met (Amsterdam II or Revised Bethesda), and a detailed family history including at-risk relatives to support medical necessity for germline testing.

MSI or IHC results
BRAF V600E or MLH1 promoter methylation results (if performed)
Clinical criteria met (Amsterdam II or Revised Bethesda)
Family history including at-risk relatives

Prior Authorization

Benefits subject to member's plan & medical necessity

Coverage and payment depend on the member’s benefit plan and medical necessity. Even if testing meets the policy’s medical necessity criteria, verify benefit eligibility and obtain prior authorization when required by the specific product.

Background & Evidence

Hereditary colorectal cancer syndromes described include: FAP, characterized by hundreds to thousands of adenomatous colon polyps beginning in adolescence and caused by germline APC variants (autosomal dominant); attenuated FAP with fewer polyps and later onset; MAP (MUTYH-associated polyposis), an autosomal recessive condition with biallelic MUTYH variants often producing attenuated polyposis and substantial CRC risk; Lynch syndrome, caused by germline variants in MMR genes (MLH1, MSH2, MSH6, PMS2) and accounting for ~3–5% of CRC with high lifetime cancer risks; JPS, associated with SMAD4 or BMPR1A variants and diagnosed clinically by multiple juvenile polyps or ≥5 juvenile colonic polyps; and PJS, associated with STK11 variants, characteristic mucocutaneous pigmentation, and hamartomatous polyps.

Tumor screening strategies to guide germline testing include MSI testing and IHC for MMR proteins as initial evaluations in CRC and endometrial cancer; either test may be used and IHC can point to the likely MMR gene to sequence. When IHC shows loss of MLH1, reflex somatic testing for BRAF V600E or MLH1 promoter methylation can distinguish sporadic tumors from Lynch syndrome and reduce unnecessary germline MLH1 sequencing. Because genetic and phenotypic differences affect management, targeted familial variant testing (testing unaffected relatives for a known pathogenic family variant) and gene-specific testing strategies (e.g., targeted MUTYH hotspot testing Y165C/G382D in some populations, EPCAM testing when MSH2 protein is absent but no MSH2 germline variant is found) are recommended to maximize diagnostic yield and guide appropriate surveillance and prophylactic interventions.

Evidence summary (brief.evidence items)

EGAPP recommendationRecommend testing all newly diagnosed CRC patients with MSI or IHC screening

Revision History

11/18/2020added

Added code 0238U.

10/01/2023added

Added new diagnosis codes D1391 and D1399 to the policy.

06/10/2024; effective 07/01/2024added

Added code 0474U.

Policy Summary

PayerCapital Bluecross

PolicyGenetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes

Policy CodePolicy MP 5.013

Change TypeAdministrative code and content updates

Effective Date12/1/2025

Next Review Date

SourceLink

On This Page

Individuals with classical FAP for the sole purpose of confirming the clinical diagnosis (considered investigational).

Any other situation not specified as medically necessary above (insufficient evidence of clinical benefit).

MUTYH Testing - Medically Necessary

Genetic testing for MUTYH gene variants may be considered medically necessary when ALL of the following are met. Note: MUTYH-associated polyposis is autosomal recessive; family-history context (no affected parents/children) is informative.

Individuals with a differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome and a negative result for APC gene variants.

Clinical note: A family history with no parents or children affected by FAP is consistent with MAP and supports testing.

MUTYH Testing - Investigational

Genetic testing for MUTYH gene variants is considered investigational when ALL of the following apply.

Any situation not described as medically necessary above (insufficient evidence of benefit).

MMR Gene Testing (MLH1, MSH2, MSH6, PMS2) - Medically Necessary

Genetic testing for MMR genes (MLH1, MSH2, MSH6, PMS2) may be considered medically necessary when any one of the following populations or conditions is met. When no affected family members have been tested, a validated risk model showing ≥5% predicted risk (e.g., MMRpro, PREMM5, MMRpredict) may support testing.

Individuals with colorectal cancer (CRC) whose tumor testing suggests germline MMR deficiency (e.g., abnormal IHC or high MSI) or who meet clinical criteria for Lynch syndrome (see Policy Guidelines).

Individuals with endometrial cancer whose tumor testing suggests germline MMR deficiency or who meet clinical criteria for Lynch syndrome (see Policy Guidelines).

At-risk relatives of individuals with a known pathogenic/likely pathogenic MMR gene variant.

Individuals with a differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome (testing choice guided by presentation).

Individuals without CRC but with a family history meeting Amsterdam or Revised Bethesda criteria, or with documentation of ≥5% predicted risk on a validated risk model, when no affected family members have been tested for MMR variants.

MMR Gene Testing - Investigational

Genetic testing for germline MMR gene variants is considered investigational when ALL of the following apply.

Any situation not described as medically necessary above (insufficient evidence to support clinical benefit).

EPCAM Testing - Medically Necessary

Genetic testing for EPCAM gene variants may be considered medically necessary when any one of the following is met. Note: EPCAM deletions cause MSH2 silencing and testing is appropriate when sequencing for MSH2 is negative but clinical/tumor findings suggest EPCAM-related Lynch syndrome.

Individuals with CRC when tumor tissue shows lack of MSH2 protein expression by IHC and germline testing is negative for an MSH2 variant.

Individuals with CRC with high-level MSI and negative germline testing for MSH2, MLH1, PMS2, and MSH6.

At-risk relatives of individuals with a known EPCAM pathogenic/likely pathogenic variant.

Individuals without CRC but meeting Amsterdam or Revised Bethesda criteria, or with ≥5% predicted risk on a validated model, when no affected family members have been tested for MMR variants and MMR sequencing is negative.

EPCAM Testing - Investigational

Genetic testing for EPCAM gene variants is investigational when ALL of the following apply.

Any situation not meeting the medically necessary criteria above (insufficient evidence of benefit).

BRAF V600E or MLH1 Promoter Methylation - Somatic Testing Medically Necessary

Somatic testing for BRAF V600E or MLH1 promoter methylation may be considered medically necessary when ALL of the following are met.

Used to exclude a diagnosis of Lynch syndrome when MLH1 protein is not expressed in a colorectal tumor by immunohistochemistry.

BRAF/MLH1 Methylation Testing - Investigational

Somatic testing for BRAF V600E or MLH1 promoter methylation is investigational when ALL of the following apply.

Use in any other situation to exclude Lynch syndrome or for other purposes not described as medically necessary (insufficient evidence).

SMAD4 and BMPR1A Testing - Medically Necessary

Genetic testing for SMAD4 and BMPR1A gene variants may be considered medically necessary when any one of the following major criteria is met. At-risk relatives of affected individuals also meet criteria.

Clinical diagnosis of juvenile polyposis syndrome defined by any one of: at least five juvenile polyps in the colon; multiple juvenile polyps elsewhere in the gastrointestinal tract; or 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.

SMAD4 and BMPR1A Testing - Investigational

Genetic testing for SMAD4 and BMPR1A gene variants is investigational when ALL of the following apply.

Any situation not meeting the medically necessary criteria above (insufficient evidence of clinical benefit).

STK11 Testing - Medically Necessary

Genetic testing for STK11 gene variants may be considered medically necessary when any one of the following major criteria is met. At-risk relatives of affected patients also meet criteria.

Clinical diagnosis of Peutz-Jeghers syndrome based on presence of any two of: two or more histologically confirmed Peutz-Jeghers polyps; characteristic mucocutaneous pigmentation; or a family history of Peutz-Jeghers syndrome.

At-risk relative of a patient suspected of or diagnosed with Peutz-Jeghers syndrome.

STK11 Testing - Investigational

Genetic testing for STK11 gene variants is investigational when ALL of the following apply.

Any situation not meeting the medically necessary criteria above (insufficient evidence of benefit).

Other Gene Variants

Genetic testing for all other gene variants for Lynch syndrome or colorectal cancer is considered investigational.

Testing for any gene variants not specifically listed as medically necessary elsewhere in this policy (insufficient evidence to conclude benefit).

Genetic Counseling

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

Genetic counseling provided before and after testing to support informed decision-making and result interpretation.

Evaluation for Lynch Syndrome - Tumor Screening Strategy

Tumor-screening strategy for evaluation of Lynch syndrome — use the following workflow when evaluating patients with CRC or endometrial cancer.

Initial tumor testing with either microsatellite instability (MSI) testing or immunohistochemistry (IHC) for MMR proteins; both tests are not required.

If MLH1 protein is not expressed by IHC, reflex testing with somatic BRAF V600E and/or MLH1 promoter methylation may be performed to help exclude sporadic MLH1 loss before germline testing.

Proceed to germline MMR gene sequencing guided by tumor testing results; when indicated begin with MLH1 and MSH2 unless IHC indicates otherwise.

Standard sequencing may not detect large deletions/duplications — if MMR variants are suspected based on IHC/MSI but sequencing is negative, perform additional testing for large deletions or duplications.

Population Selection for Lynch Testing

Population selection for Lynch syndrome testing/screening — consider any one of the following.

All newly diagnosed colorectal cancer patients should be considered for tumor screening for Lynch syndrome.

First-degree relatives (and other at-risk relatives depending on pedigree size) of individuals with Lynch syndrome or a known pathogenic/likely pathogenic MMR/EPCAM variant.

Proband testing: when possible, perform initial genetic testing in an affected family member so subsequent testing in unaffected relatives can target the familial variant.

Individuals without CRC who meet Amsterdam or Revised Bethesda criteria, or who have ≥5% predicted risk on a validated model when no affected family members have been tested.

Coding and Coverage Context

Coding and Coverage Context — provider-impact and billing/coding rules to follow for testing described in this policy.

Prior authorization: Obtain prior authorization as required by payer policy for genetic testing panels and single-gene tests per contractual rules.

Documentation requirements: Include clinical indication, family history (pedigree when available), tumor testing results (MSI/IHC/BRAF/methylation) if applicable, and targeted familial variant information when testing at-risk relatives.

Billing guidance: When targeted familial variant testing is performed for an unaffected relative, bill for targeted/familial variant code(s) rather than full sequencing panel; when reflex tumor testing (MSI/IHC) directs single-gene germline testing, document rationale to support medical necessity.

Code and claim edits: Tests reported without required clinical documentation or performed outside the medically necessary criteria may be denied as not medically necessary.

Benefit application: When an affected family member is available, initial testing should be performed in that affected member to enable targeted testing in relatives and to avoid unnecessary broader testing.

Billing Rule

Use listed procedure codes

Report genetic testing using the applicable procedure codes listed in the coding information section. Identification of a code in the policy does not by itself denote coverage—coverage is determined by the member’s benefit terms and medical necessity.

0157U
0158U
0159U
0160U
0161U
0162U
0238U
0474U
81201
81202
81203

Documentation Required

Medical necessity determination

Providers must ensure genetic testing is medically necessary for the clinical scenario and supported by the member’s benefit information prior to ordering or billing; listing of a code in the policy does not guarantee coverage.

Billing Rule

Code usage per policy coding list

Report the procedure and molecular diagnostic codes listed in the policy coding section when applicable. Note that some code entries are administrative or duplicate and coding is subject to change; the identification of a code does not alone denote coverage.

0157U
0158U
0159U
0160U
0161U
0162U
0238U
0474U
81201
81202
81203
81210
81288
81292
81293
81294
81295
81296
81297
81298
81299
81300
81301
81317
81318
81319
81403
81435

MSI sensitivity (MLH1/MSH2)≈89%

MSI sensitivity (MSH6)≈77%

IHC sensitivity (MLH1/MSH2/MSH6)≈83%

IHC/MSI false-negative rate5%-10%

NCCN guideline versions referencedColon Cancer v2.2023; Genetic/Familial High-Risk Assessment: Colorectal v3.2024; Colorectal Cancer Screening v1.2024

Key validation models citedPREMM5 / PREMM(1,2,6) and MMRpro / MMRpredict (validation references: Kastrinos et al.)

At-risk relatives: Primarily refers to first-degree relatives, though inclusion of extended relatives may be appropriate in small pedigrees or specific family histories; policy guidelines give examples of family-history patterns that warrant consideration for testing.

Amsterdam II Clinical Criteria: A stringent family-history definition for Lynch syndrome requiring three or more relatives with related cancers across generations, with one a first-degree relative of the other two and at least one diagnosed before age 50 (all criteria must be fulfilled).

Revised Bethesda Guidelines: Less strict than Amsterdam II and intended to identify which CRC patients should have tumor MSI and/or IHC testing; fulfillment of any single Bethesda criterion meets the guideline for tumor testing.

MAP: MUTYH-associated polyposis is an autosomal recessive condition in which biallelic MUTYH variants confer a high lifetime CRC risk; family patterns without affected parents or children can suggest MAP.

SCREENING: Refers to evaluating a patient for disease (such as cancer) before clinical signs appear — e.g., using MSI or IHC tumor tests to identify patients who should have germline MMR testing.

12/10/2024; removed effective 01/01/2025

12/13/2024revised

Removed NCCN statement.

01/13/2025removed

Removed code 0421U.

05/15/2025revised

Consensus Review. No changes to policy statement.

09/02/2025; effective 10/01/2025added

Added ICD-10 code Z15.060.

10/22/2025revisedLatest

Removed Benefit Variations Section and updated Disclaimer.