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ModifiedColorado Rocky Mountain Health PlansPolicy CS049.AB

Genetic Testing for Hereditary Cancer

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Defines medical necessity and coverage criteria for germline genetic testing for hereditary cancer syndromes, and lists applicable procedure codes; applies to Colorado Rocky Mountain Health Plans membership except where state-specific policies override.

Policy Summary

PayerColorado Rocky Mountain Health Plans

PolicyGenetic Testing for Hereditary Cancer

Policy CodePolicy CS049.AB

Change TypeCoding update — added 0651U

Effective DateAug 1, 2026

Last ReviewAug 1, 2026

Next Review DateN/A

Key ActionProvide medical records and a contemporaneous pedigree/family history with testing requests; prior authorization may be required when guideline-based indications are used.

SourceLink

POLICY UPDATE CHANGES

Updated list of applicable CPT codes to reflect quarterly edits and added code 0651U.

Archived previous policy version CS049.AA.

5+Minimum genes

≤65BRCA age cutoff

2.5% / 5%Risk thresholds

13.3%PGV in solid tumors

0651UCPT update

InsufficientPRS evidence

Coverage Criteria and Indications

inv-01: Individuals with a personal history of a primary solid tumor — multigene panel indicated

Multigene hereditary cancer panel testing for individuals with a personal history of a Primary Solid Tumor (excluding basal or squamous cell skin cancer) is proven and medically necessary when at least one of the following is met:

Personal history qualifying features: Individual has a personal history of at least one of the following: Breast cancer diagnosed ≤50 years; Metastatic breast cancer; Multiple primary breast cancers (including bilateral); Triple-negative breast cancer; Lobular breast cancer with personal or family history of diffuse gastric cancer; Breast cancer and Ashkenazi Jewish ancestry; Breast cancer in a person assigned male at birth; Breast cancer with unknown or limited family history; Breast or prostate cancer plus at least one first- or second-degree relative with a BRCA-related cancer; Ovarian cancer (including fallopian tube, primary peritoneal, sex‑cord tumor with annular tubules, hypercalcemic‑type small cell carcinoma of the ovary); Serous tubal intraepithelial carcinoma; Pancreatic cancer; Metastatic prostate cancer; Lynch syndrome–associated cancer; Neuroendocrine tumor (e.g., adrenocortical carcinoma, paraganglioma, pheochromocytoma); Malignant phyllodes tumor; Renal cell carcinoma meeting any of: diagnosed ≤46 years; bilateral or multifocal tumors; one or more first‑ or second‑degree relatives with renal cell carcinoma; personal or family history of mesothelioma or uveal melanoma; Angiomyolipoma plus another TSC feature; Succinate dehydrogenase–deficient renal cell carcinoma histology; At least two different primary solid tumors (excluding basal/squamous skin cancer).

From policy list of qualifying personal history features

Policy Summary

PayerColorado Rocky Mountain Health Plans

PolicyGenetic Testing for Hereditary Cancer

Policy CodePolicy CS049.AB

Change TypeCoding update — added 0651U

Effective DateAug 1, 2026

Last ReviewAug 1, 2026

Next Review DateN/A

Key ActionProvide medical records and a contemporaneous pedigree/family history with testing requests; prior authorization may be required when guideline-based indications are used.

SourceLink

On This Page

inv-02: Personal history plus family history — multigene panel indicated

Multigene testing is medically necessary when the individual has a personal history of a primary solid tumor and a family history meeting at least one listed criterion:

Family history qualifying features: At least one close blood relative with a Lynch syndrome–associated cancer; OR at least one close blood relative diagnosed with a primary solid tumor at age ≤40 years; OR at least two close blood relatives (in addition to the proband) on the same side of the family diagnosed with any primary solid tumor (excluding basal/squamous skin cancer).

Policy family-history criteria

inv-03: Personal history with tumor-based indicators — germline testing indicated

Multigene testing is medically necessary when an individual with a personal history of a primary solid tumor has at least one tumor-based indicator or relevant risk score:

Tumor-based indicators and risk scores: A pathogenic variant detected in tumor tissue that has clinical implications if present in the germline (examples include BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, MUTYH, PALB2, PMS2, RAD51C, RAD51D, RET, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TSC2, VHL, APC, PTEN, RB1, TP53); OR tumor testing demonstrating microsatellite instability–high (MSI‑H) or loss/absence of mismatch repair proteins on IHC (MLH1, MSH2, MSH6, PMS2); OR renal cell carcinoma with histologies associated with hereditary syndromes (multifocal papillary, FH‑deficient, Birt‑Hogg‑Dubé, SDH‑deficient, angiomyolipoma with additional TSC feature); OR risk model thresholds: Tyrer‑Cuzick, BRCAPRO, or CanRisk score ≥2.5% for BRCA1/2, or PREMM5/MMRpro/MMRpredict score ≥2.5% for Lynch syndrome gene mutation.

Includes enumerated genes, histologies, and model thresholds

inv-04: Individuals with no personal history of a primary solid tumor — testing for unaffected individuals

Genetic testing (multigene panel or BRCA1/2) for individuals without a personal history is medically necessary if at least one of the following family‑history or risk‑score criteria is met:

First-degree relative criteria: At least one first‑degree relative with: two or more different primary solid tumors (excluding basal/squamous skin cancer); OR a Lynch syndrome–associated cancer; OR a neuroendocrine tumor (e.g., adrenocortical carcinoma, paraganglioma, pheochromocytoma); OR at least one first‑ or second‑degree relative with: breast cancer diagnosed ≤50 years, triple‑negative breast cancer, breast cancer in a person assigned male at birth, metastatic prostate cancer, ovarian cancer (including fallopian tube or primary peritoneal), or pancreatic cancer.

Policy enumerated relatives‑based triggers

Second-degree relative and patterned family history criteria: At least one second‑degree relative with two or more Lynch syndrome–associated cancers or an LS‑associated cancer diagnosed ≤50 years; OR family patterns such as two or more second‑degree relatives on the same side with Lynch cancers; OR two or more first‑ or second‑degree relatives on the same side with renal cell carcinoma; OR three or more close blood relatives on the same side with any primary solid tumor (excluding basal/squamous skin cancer); OR Ashkenazi Jewish ancestry plus a close blood relative with a BRCA‑related cancer; OR family member meeting diagnostic criteria for polyposis (≥10 adenomas) with affected family member unwilling/unable to test; OR personal colorectal polyposis with ≥10 adenomas; OR risk model thresholds: Tyrer‑Cuzick/BRCAPRO/CanRisk ≥5% for BRCA1/2 or PREMM5/MMRpro/MMRpredict ≥5% for Lynch syndrome.

Policy enumerated family‑history and risk‑score triggers

inv-05: Pediatric cancer

Testing in young individuals

Cancer diagnosed ≤18: Multigene hereditary cancer panels are proven and medically necessary for individuals diagnosed with cancer at age 18 years or younger.

Policy explicit pediatric provision

inv-06: Not covered / unproven tests — criteria node for experimental/unproven indications

Unproven or not medically necessary: Multigene hereditary cancer panels are unproven and not medically necessary for indications other than those explicitly listed; RNA panel testing for hereditary cancers is unproven and not medically necessary for all indications; genetic testing for polygenic risk scoring for hereditary cancers is unproven and not medically necessary for all indications; whole‑exome and whole‑genome sequencing for the purpose of identifying hereditary cancer syndromes or risk is unproven and not medically necessary for all indications.

Policy exclusions for specific test types

inv-07: General medical necessity — covered when ALL of the following are met

Covered when ALL of the following are met

General coverage conditions: Testing is generally recommended when (1) there is a personal or family history consistent with hereditary cancer susceptibility, (2) the test can be adequately interpreted, and (3) the results can be used to diagnose or influence medical management of the individual or at‑risk family members.

From policy Description of Services.

inv-08: Multigene panel consideration — Consider MGPT when ALL of the following apply

Consider multigene panel testing when ALL of the following apply

Panel vs single‑gene testing: Multigene hereditary cancer panels may be appropriate when family history suggests multiple possible hereditary cancer syndromes or when stepwise single‑gene testing would be inefficient; panels often include low‑ or moderate‑risk genes that may generate variants of uncertain clinical utility, and the ordering clinician should weigh potential benefits against harms (uncertain findings and downstream interventions).

Policy notes pros/cons of panels and potential for uncertain findings.

inv-09: Guideline-based clinically indicated testing

Covered when criteria per guideline indications are met (NCCN and specialty society recommendations):

General indications: Testing is clinically indicated in any of these situations: presence of a blood relative with a known P/LP variant; prior limited negative testing with ongoing suspicion and desire for multigene testing; a P/LP variant identified on tumor genomic testing that may be germline; testing to aid systemic therapy or surgical decision‑making; or meeting criteria for Li‑Fraumeni, Cowden/PTEN hamartoma tumor syndrome, or Lynch syndrome.

Based on NCCN general testing criteria (v1.2026).

Breast cancer specific indications: Testing for high‑penetrance breast cancer genes (BRCA1, BRCA2, CDH1, PALB2, PTEN, STK11, TP53) is clinically indicated when patient meets one or more features: diagnosis ≤50 years; triple‑negative breast cancer (particularly ≤60 years); multiple primary breast cancers; male breast cancer; Ashkenazi Jewish ancestry; a close relative with early‑onset breast, ovarian, pancreatic, or prostate cancer; ≥3 diagnoses of breast/prostate cancer on same side of family; or prior probability >5% for BRCA1/2 based on models (e.g., Tyrer‑Cuzick, BRCAPRO, CanRisk).

Includes NCCN detailed breast criteria.

Ovarian cancer specific indications: Testing for ovarian cancer susceptibility genes (e.g., BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, MLH1, MSH2, MSH6, EPCAM, PALB2) is clinically indicated for patients with epithelial ovarian cancer at any age, selected nonepithelial ovarian cancers, or unaffected individuals with a first‑ or second‑degree relative with epithelial ovarian cancer; consider testing when prior probability models indicate >5% BRCA risk.

Per NCCN and ASCO ovarian cancer guideline.

Pancreatic cancer specific indications: Testing for pancreatic cancer susceptibility genes (e.g., ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, EPCAM, PALB2, STK11, TP53) is clinically indicated for patients with exocrine or neuroendocrine pancreatic cancer or those with a first‑degree relative with exocrine pancreatic cancer.

Per NCCN pancreatic criteria.

Prostate cancer specific indications: Testing for prostate cancer susceptibility genes (e.g., ATM, BRCA1, BRCA2, CHEK2, HOXB13, PALB2, TP53) is indicated for patients with metastatic or high/very‑high risk prostate cancer or with family/ancestry features such as relatives with early‑onset breast cancer, ovarian, pancreatic cancer, or multiple affected relatives; testing may be considered for earlier‑onset or certain histologies.

Per NCCN and ASCO guidance for metastatic prostate cancer.

inv-10: Guideline-based testing criteria — NCCN, CGA-IGC/NSGC and others

Guideline‑based indications for germline multigene testing or syndrome‑specific testing (NCCN, CGA‑IGC/NSGC, and others):

NCCN minimum gene list for CRC MGPT: When germline MGPT is used for colorectal cancer, panels should include at minimum APC, MUTYH, MLH1, MSH2, MSH6, PMS2, EPCAM, BMPR1A, SMAD4, PTEN, STK11, and TP53; use additional genes based on age, phenotype, and family history.

Use of additional genes depends on age, phenotype, and family history.

NCCN minimum gene list for endometrial cancer MGPT: For endometrial cancer, germline MGPT should include at minimum MLH1, MSH2, MSH6, PMS2, EPCAM, PTEN, and BRCA1/2; add genes per clinical context.

Additional genes per clinical context.

CGA‑IGC/NSGC Lynch syndrome evaluation criteria: Evaluate for Lynch syndrome when there is a known germline MMR P/LP variant in the family OR a personal history of CRC or EC with age <50, tumor dMMR, another LS‑related cancer, or family history meeting degree/number criteria; predictive model probability thresholds (e.g., PREMM5, MMRpro) are used to guide testing decisions.PREMM5/MMRpro ≥5% (consider ≥2.5% in select contexts)

Patients with PREMM5 ≥2.5% may be considered; selection thresholds vary by context.

NCCN Lynch syndrome testing criteria: Test when known LS PV in family; personal LS‑related cancer diagnosed ≤49; synchronous/metachronous LS‑related cancer; relevant family history patterns; predictive model risk ≥5% (with allowance for 2.5% in certain clinical contexts); tumor dMMR at any age; or P/LP on tumor genomic testing with germline implications.PREMM5 thresholds: consider ≥2.5% in some patients; standard ≥5% for others.

Also consider testing for patients ≥50 if untested for dMMR or documented absence of dMMR.

Adenomatous polyposis testing criteria: Recommend testing for patients with ≥20 cumulative adenomas, family history of a known PV in an adenomatous polyposis gene, specific retinal or thyroid findings, or family unwilling/unable to test; consider testing for 10–19 adenomas or other listed features.≥20 adenomas = recommended; 10–19 adenomas = consider

Germline testing should be considered for APC PVs found on tumor‑only testing in certain contexts.

USMSTF hamartomatous polyposis testing criteria: Genetic evaluation (and MGPT if indicated) is recommended for patients with two or more lifetime hamartomatous polyps, family history of hamartomatous polyps, or associated cancers in first‑ or second‑degree relatives; specific recommendations exist for Peutz‑Jeghers and juvenile polyposis features.

Strong recommendation though quality of evidence varies.

inv-11: Empirical evidence on MGPT yield and impact

Evidence from cohort and prospective studies about yield and implications of MGPT:

MGPT yield in colorectal cancer cohorts: Coughlin et al. found 14.2% of CRC patients had ≥1 P/LP variant, 9.1% had CRC/polyposis‑associated variants, and at least 7.9% had clinically actionable variants across panel sizes; VUS rate was 38.2%.

Findings support expanding germline testing in CRC cohorts.

Universal MGPT vs guideline‑directed in CRC: Uson et al. reported universal MGPT identified additional clinically actionable findings (9.4% undetected by CRC‑specific panels) and led to management changes in ~11% of participants; cascade testing uptake was low (~16%).

Prospective multisite study results summarized.

Universal MGPT in unselected solid tumors: Samadder et al. found PGVs in 13.3% of an unselected solid tumor cohort (n=2,984) with clinically actionable findings not detected by guideline‑based testing and some treatment modifications in carriers; VUS rate was high (47.4%).

Universal testing identified additional carriers compared with guideline‑directed testing.

MGPT in pancreatic cancer: Uson et al. (pancreas cohort) found PGVs in 15.2% of participants, most commonly BRCA1/2, PALB2, ATM, CHEK2; VUS rates were high (44.4%), supporting MGPT use in pancreatic cancer for treatment selection and family counseling.

Prospective cohort evidence supports MGPT in pancreatic cancer.

inv-12: Guideline-based recommendations (ASCO, NCCN)

Guideline-based recommendations for offering germline multigene testing to patients with cancer:

Core actions: Obtain and record a comprehensive family history for all patients with cancer; offer germline multigene testing when indicated by personal or family history or when results could impact treatment, clinical trial eligibility, or family risk; ensure genetic counseling or expertise is available for ordering and interpretation.

ASCO strong recommendation; NCCN references

Situations prompting germline testing irrespective of tumor testing: Offer germline testing when a patient meets established germline testing criteria (e.g., NCCN) or when tumor testing reveals a pathogenic variant in genes listed by ASCO as triggering germline evaluation (examples: BRCA1/2, BRIP1, MLH1, MSH2, MSH6, MUTYH, PALB2, PMS2, RAD51C, RAD51D, RET, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TSC2, VHL; and additional genes in patients <30 years).

ASCO list of tumor‑detected genes prompting germline testing

Panel composition guidance: Panels should include at minimum the more strongly recommended genes for the patient's tumor type; broader panels may be used when benefits outweigh potential harms from uncertain results; smaller panels can be used initially when rapid results are needed for treatment decisions.

ASCO guidance on strongly/less strongly recommended genes per tumor type

inv-13: Clinical evidence–informed coverage considerations

Evidence‑based coverage stance summary based on reviewed studies

PRS: Evidence is insufficient to support the clinical use of polygenic risk scores (PRS) for hereditary cancer risk assessment; PRS should not be used alone to guide clinical management.

Policy states evidence for PRS is currently insufficient

RNA testing: Concurrent RNA panel testing with BRCA1/2 or multigene hereditary cancer panels has limited supporting evidence; RNA testing may clarify some splicing‑related variants and modestly increase diagnostic yield in select cases but is not validated for routine concurrent use.

Selective RNA testing may be reasonable to clarify variants after DNA testing

WES/Exome+: Exome+/WES can identify carriers of HBOC and Lynch syndrome missed by guideline‑based testing (e.g., Tapestry Exome+ found 1.24% carriers and ~39.2% of carriers did not meet NCCN criteria), but limitations (reduced CNV detection, demographic representation, downstream implementation) currently restrict routine adoption for population screening.

Exome+ findings require further study before routine adoption

Multigene hereditary cancer panels are supported when ordered for individuals who meet the policy's indicated clinical criteria (for example, persons with a qualifying personal history of a primary solid tumor, relevant tumor-based findings, or specified family-history constellations). Concurrent RNA panel testing, polygenic risk scoring (PRS), and whole-exome/whole-genome sequencing (WES/WGS/Exome+) are discussed in the evidence review but are not established as routine standard-of-care tests for hereditary cancer in the general population; the policy notes limited evidence for routine concurrent RNA panels and that Exome+/WES can identify additional carriers in population screening but has implementation limitations. Documentation of how these assays would change management is expected when they are proposed outside the policy's listed indications.

Panels that include genes with low or uncertain cancer-risk associations should be used with caution. The policy highlights that many commercial multigene panels include low- to moderate-risk genes for which clinical management recommendations are limited, increasing the likelihood of variants of uncertain significance and unclear downstream actions. Ordering clinicians should consider the evidence for each gene's association with disease and preferentially use panels targeted to the clinical scenario to avoid unnecessary follow-up.

Routine population-based BRCA1/2 testing or multigene panel testing is not recommended for individuals without a relevant personal or family history or ancestry that increases BRCA-related risk. The USPSTF guidance and the policy both advise that BRCA counseling and testing should be directed by positive screening results or documented risk, not offered routinely to average-risk individuals.

The U.S. Preventive Services Task Force recommends against routine BRCA genetic counseling or testing for women whose personal or family history and ancestry are not associated with increased BRCA1/2 risk. Individuals with positive screening results should receive genetic counseling and, if indicated, testing.

The evidence base for polygenic risk scores (PRS) in assessing hereditary cancer risk is insufficient. PRS incorporate many variants of varying and sometimes unknown significance, and current data do not support their routine clinical use to guide hereditary cancer management.

Given the current evidence limitations, PRS should not be used as a standalone clinical test to determine hereditary cancer risk or to direct management decisions. When PRS are reported, clinicians should recognize limitations in interpretation and cross-check plan coverage rules and benefit terms, since policy coverage is governed by applicable federal, state, or contractual requirements.

This Medical Policy is informational and does not itself determine coverage for an individual member. Coverage decisions are governed by the applicable federal, state, or contractual benefit plan terms, which take precedence if inconsistent with this policy.

The policy explicitly identifies RNA panel testing, polygenic risk scoring (PRS), and whole-exome/whole-genome sequencing (WES/WGS/Exome+) as approaches for which routine clinical utility is not yet established for hereditary cancer identification. RNA panels may clarify some splicing variants after DNA testing but lack evidence to support universal concurrent use; PRS and WES/WGS are considered investigational or unproven for routine hereditary cancer risk assessment outside specific, documented contexts.

Multigene panel testing applied to unselected populations—where gene–disease associations are weak or management data are limited—may have limited clinical utility and produce results that are difficult to act upon. The policy cautions against routine population-based panel testing when many included genes lack clear evidence linking variants to changes in medical management.

Routine genetic counseling and testing are not recommended for people without a relevant personal or family history or ancestry risk. The policy strongly recommends pretest genetic counseling and a detailed family-history assessment to determine whether testing is indicated and interpretable; counseling helps ensure that testing will meaningfully inform the individual's or family's medical management.

Panels that include genes supported only by limited evidence may yield uncertain results and have unclear clinical utility. The policy notes that studies and guideline reviews have identified numerous genes with low population-level effect sizes or insufficient evidence to support routine inclusion on broad panels, and therefore panel composition should be chosen to match the clinical question.

Current evidence does not support routine, concurrent RNA panel testing for all hereditary cancer panel submissions. RNA testing can clarify some splicing variants and modestly increase diagnostic yield in select cases, but the policy recommends a stepwise approach—DNA testing first with targeted RNA analysis when needed—until higher-quality evidence supports broader routine concurrent use.

Specific Covered Indications

inv-74: Germline genetic testing (single gene, known familial mutation testing, BRCA1/2, or multigene hereditary cancer panels) for individuals with personal or strong family history per policy

Germline genetic testing (single gene, known familial mutation testing, BRCA1/2, or multigene hereditary cancer panels) is covered for individuals with personal or strong family history when criteria below are met:

Covered indications overview: Testing is indicated for individuals with a personal history of qualifying tumors, individuals with qualifying family history patterns, individuals with tumor‑based findings suggesting a germline variant, unaffected individuals meeting degree/number family criteria or risk model thresholds, pediatric cancer patients (≤18 years), and when testing results will influence medical or surgical management or family risk assessment.

Consolidated summary of covered indications

inv-75: Personal or family history suggestive of hereditary breast, ovarian, pancreatic, prostate, colorectal, endometrial, gastric, or other syndromes

Personal or family history suggestive of hereditary cancer syndromes includes the following tumor types and associated genes:

Syndromes and associated tumor types: Hereditary breast, ovarian, pancreatic, prostate, colorectal, endometrial, gastric, neuroendocrine/adrenal, renal cell carcinoma, and other syndromes are included; implicated genes include but are not limited to BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN, STK11, CHEK2, ATM, RAD51C, RAD51D, BRIP1, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH, BMPR1A, SMAD4, and TP53.

Policy lists tumor types and exemplar genes

inv-76: Testing when patient or relatives meet guideline-based criteria or results will inform therapy/surgery

Testing is covered when patient or relevant relatives meet guideline‑based criteria or when results will inform therapy or surgical decisions:

Guideline‑based or management‑impact testing: Testing is indicated when patient or relatives meet NCCN/ASCO guideline criteria for hereditary breast, ovarian, pancreatic, prostate, or colorectal cancer syndromes, or when test results are expected to influence systemic therapy (e.g., PARP inhibitor use), surgical planning, or clinical trial eligibility.

Policy references NCCN and ASCO guidance

inv-77: MGPT supported in colorectal cancer patients (evidence of clinically actionable variants)

MGPT is supported in colorectal cancer patients by cohort and prospective studies demonstrating clinically actionable variant detection across ages and panel sizes:

CRC MGPT evidence: Studies report clinically actionable P/LP variant rates in CRC cohorts (Coughlin et al.: 14.2% with ≥1 P/LP; overall clinically actionable rate ≥7.9%) and prospective universal MGPT (Uson et al.) found additional actionable findings not captured by guideline‑directed panels, with some management changes resulting.

Evidence supports MGPT use in CRC patients

inv-78: Individuals meeting NCCN/CGA-IGC/NSGC criteria for hereditary CRC/EC syndromes including tumor dMMR and model thresholds

Individuals meeting NCCN or CGA‑IGC/NSGC criteria for hereditary CRC/EC syndromes should be evaluated and tested according to guideline thresholds:

NCCN/CGA‑IGC/NSGC Lynch and CRC/EC criteria: Evaluate and offer MGPT when personal/family history meets guideline patterns (e.g., early‑onset CRC/EC, multiple affected relatives, synchronous/metachronous LS cancers), when tumor dMMR is present, when a known familial PV exists, or when predictive model risk reaches recommended thresholds (PREMM5/MMRpro/MMRpredict ≥5% standard, with consideration at ≥2.5% in some contexts).PREMM5/MMRpro ≥5% (consider ≥2.5% in select cases)

NCCN lists minimum gene sets for CRC/EC panels

inv-79: Patients meeting adenomatous or hamartomatous polyposis syndrome testing criteria

Patients meeting adenomatous or hamartomatous polyposis syndrome criteria should undergo genetic evaluation and testing when indicated:

Polyposis testing triggers: Recommend testing for patients with ≥20 cumulative adenomas, family history of a known PV in an adenomatous polyposis gene, multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium, cribriform‑morular variant thyroid cancer, or when family members with diagnostic polyposis are unable/unwilling to test; consider testing for 10–19 adenomas or other listed features.≥20 adenomas = recommended; 10–19 = consider

USMSTF and NCCN guidance referenced

inv-80: Individuals with pheochromocytomas/paragangliomas should undergo MGPT given high heritability

Individuals with pheochromocytomas/paragangliomas (PPGL) have a high heritability and should undergo MGPT:

PPGL testing indication: Offer MGPT to individuals with PPGL because of high diagnostic yield across multiple genes (SDHx, VHL, RET, NF1, FH, TMEM127, MAX, etc.); NGS is preferred to capture varied genetic causes and testing should include at least FH, NF1, RET, SDHB, SDHD, and VHL with consideration of additional genes per guideline.

Review articles and guideline recommendations support universal testing in PPGL

inv-81: Individuals with pancreatic cancer or unselected solid tumors may be offered MGPT

Individuals with pancreatic cancer or unselected solid tumors may be offered MGPT due to appreciable rates of pathogenic germline variants (PGVs) that can affect treatment and family counseling:

Pancreatic and universal solid tumor testing: Prospective studies reported PGV prevalence ~15% in pancreatic cancer (Uson et al.) and ~13% across unselected solid tumors (Samadder et al.), with clinically actionable findings that in some cases changed therapy; MGPT is reasonable for pancreatic cancer and may be considered more broadly when clinical context supports it.

Study evidence summarized in policy

inv-82: Patients meeting guideline criteria when results could impact treatment, trial eligibility, or family risk

Offer germline testing when results could impact treatment, trial eligibility, or management of other cancer risks and when guideline criteria are met:

Testing for management impact: Offer germline MGPT when results could affect systemic therapy (e.g., PARP inhibitor eligibility), surgical decision‑making, enrollment in clinical trials, management of risk for other cancers, or identification of actionable variants for relatives; testing should align with NCCN/ASCO criteria and include recommended gene sets for the tumor type.

ASCO/NCCN recommendations referenced

inv-83: All patients with cancer should have recorded family history; offer MGPT when indicated including recommended gene sets

All patients with cancer should have a recorded family history; when MGPT is indicated, panels should include at least the strongly recommended genes:

Family history and panel composition: Obtain and record a comprehensive family history for all patients with cancer; offer MGPT when indicated and ensure the panel includes at minimum the more strongly recommended genes for that tumor type (e.g., BRCA1/2 and Lynch genes for many cancers), with broader panels used selectively when benefits outweigh risks.

ASCO strong recommendation

inv-84: Exome+/WES screening can identify HBOC/LS carriers including individuals not meeting NCCN criteria — implications and limits noted

Exome+/WES used for germline screening can identify HBOC and Lynch syndrome carriers not meeting NCCN criteria, but limitations exist:

Exome+/WES screening considerations: Exome+/WES can detect HBOC and LS carriers missed by guideline‑based testing (Tapestry Exome+ found 1.24% carriers and ~39.2% did not meet NCCN criteria), but limitations include lower CNV detection, demographic representation concerns, and the need for confirmatory testing and careful implementation prior to routine population screening.

Evidence from Tapestry/Exome+ summarized

inv-85: Hereditary cancer genetic testing across multiple tumor types referenced to NCCN and guideline sources

Hereditary cancer genetic testing indications and recommended gene inclusions are referenced to NCCN and other guideline sources:

Guideline‑referenced tumor types and gene lists: Coverage and testing recommendations align with NCCN/ASCO/USMSTF/NSGC guidance for cancers including colorectal, endometrial, gastric, neuroendocrine/adrenal, pancreatic, prostate, breast, ovarian and kidney cancers; specific minimum gene lists and more/less strongly recommended gene groupings are provided in the cited guidelines and referenced in the policy.

Policy points to external guideline tables for detailed gene lists

Member Eligibility and Documentation Requirements

Coverage for unaffected (asymptomatic) individuals requires demonstration of the family-history patterns enumerated in the policy (for example, qualifying first- or second-degree relative constellations, Ashkenazi Jewish ancestry plus a close relative with a BRCA-related cancer, or predictive-model thresholds when specified). A contemporaneous pedigree and detailed family history documenting ages at diagnosis and affected relatives is expected to support eligibility.

When testing an unaffected person, coverage is conditioned on meeting one or more of the family-history criteria described in the policy (such as multiple affected relatives on the same side of the family, relatives with specific early-onset cancers, or a relative meeting diagnostic criteria for a polyposis syndrome who cannot be tested). Providers should submit pedigree documentation with the request to confirm eligibility.

Operational eligibility nodes include use of validated risk-prediction thresholds for selected models: for BRCA1/2 risk, tools such as Tyrer‑Cuzick, BRCAPRO, or CanRisk are referenced; for Lynch syndrome, PREMM5, MMRpro, or MMRpredict are referenced. The policy applies risk thresholds of ≥2.5% (in certain personal-history contexts) and ≥5% (for unaffected individuals) as described in the detailed criteria.

Eligibility narratives in the policy group related entries: multigene testing is medically necessary for individuals with qualifying personal cancer histories, for unaffected relatives who meet specified family-history patterns or risk-model thresholds, and for pediatric patients diagnosed with cancer at age ≤18, per the enumerated criteria. The expectation is that documentation will substantiate these findings.

The policy reiterates that unaffected individuals meeting family-history criteria or model thresholds (e.g., Tyrer‑Cuzick/BRCAPRO/CanRisk or PREMM5/MMRpro/MMRpredict at the stated cutoffs) are eligible for BRCA1/2 testing or MGPT as appropriate. Providers should indicate which model and score support the request.

Patients who previously had limited or single-gene testing but continue to meet testing criteria may be eligible for multigene panel testing. The policy references studies showing additional pathogenic variants detected after prior negative testing and supports subsequent MGPT when clinical suspicion persists.

Explicitly, prior limited BRCA1/2 testing that was negative does not preclude subsequent MGPT if the patient meets additional criteria (for example, bilateral disease, multiple primaries, or concordant family history); evidence shows MGPT can detect additional clinically relevant variants in such populations.

The policy states that patients who previously had single-gene testing and still meet the policy criteria may proceed to MGPT; testing an affected relative first is recommended when feasible to maximize diagnostic yield and interpretability.

Operational eligibility also incorporates age thresholds and syndrome-specific triggers described in the policy (for example, pediatric cancer provision for diagnosis at ≤18 years and tumor histology–based criteria for renal cell carcinoma and PPGL), which should be documented in the clinical record submitted with the testing request.

Additional operational notes emphasize that testing should be ordered by clinicians able to obtain a detailed family history and perform a thorough physical exam, and that pedigree/personal history documentation may be required to adjudicate coverage.

When DNA testing reveals variants of uncertain significance or potential splicing variants, selective RNA testing may be reasonable to clarify classification; the policy supports selective use of RNA analysis rather than routine concurrent RNA panels.

Other operational nodes referenced in the eligibility section include use of family-history patterns (first-, second-, and third-degree relatives), ages at diagnosis, and phenotype features needed to determine whether testing criteria are met.

The policy groups duplicate inventory entries for clarity and consistently requires documentation supporting the family-history or tumor-based criteria cited in the eligibility rules.

Patients who previously had limited testing that did not include a broader panel remain eligible for MGPT if they continue to meet the policy's clinical criteria; the policy cites evidence that additional P/LP variants are identified on expanded testing in select populations.

Pretest genetic counseling is strongly recommended as part of establishing eligibility and ensuring informed consent; counseling helps document the rationale for testing and the implications of potential results for the patient and family members.

Provider Actions, Documentation & Authorization

Documentation Required

Provide medical records and pedigree with test request

Medical records and a contemporaneous pedigree/family history drawing using standardized nomenclature may be required with the testing request; medical records documentation is used to assess whether the member meets clinical criteria for coverage but does not guarantee coverage.

Submit pedigree drawing/diagram in contemporaneous medical records with the request (NCCN format)
Provide clinical records supporting personal and family history to demonstrate criteria are met

Billing Rule

Use applicable CPT/PLA/unlisted codes when ordering/billing

Reference the policy's listed procedure, PLA, and unlisted molecular pathology codes when ordering and billing hereditary cancer testing; applicable codes include exome/genome and molecular pathology CPT/PLA codes and 81479 for unlisted procedures.

Use listed codes (examples in policy: 0213U, 0214U, 0215U, 0265U, 0266U, 81416–81417, 81425–81427, 81479)
Ensure coding matches the test performed (exome/genome vs multigene panel vs unlisted molecular procedure)

Prior Authorization

Obtain prior authorization for guideline-indicated hereditary cancer testing

Prior authorization is expected for hereditary cancer testing conducted for guideline-supported indications (e.g., known familial P/LP variant, prior limited negative testing with ongoing suspicion, tumor-identified variants with germline implications, or when testing will influence systemic or surgical therapy).

Document guideline-based indication (e.g., NCCN criteria, known family PV, tumor PV with germline implication)
Provide prior testing history and rationale when requesting authorization

Note

Prior authorization note — involve genetics expertise

Although the policy does not provide additional procedural prior authorization steps, it emphasizes offering MGPT with professional genetic expertise and selecting panels based on clinical factors; involve genetics expertise when planning testing.

Ensure ordering clinician documents access to genetic counseling or genetics expertise
Select panel composition based on age, phenotype, and family history to support authorization

Prior Authorization

Consider guideline-based testing when results will affect care or family risk

Order germline multigene testing when guideline criteria are met and when results could impact treatment, clinical trial eligibility, management of other cancer risks, or family members; document guideline criteria to support testing.

Provide documentation showing testing could affect therapy decisions or trial eligibility
Reference specific guideline criteria (e.g., NCCN/ASCO) in the request

Prior Authorization

Prior authorization and documentation required for Exome+/WES

When ordering Exome+/WES for germline screening outside standard guideline criteria, prior authorization should request documentation of personal/family history and clinical rationale because population screening can identify carriers who would not meet NCCN criteria.

Include chart review or family history demonstrating why Exome+/WES is indicated
Explain how results would change management if testing is outside standard guidelines

Billing Rule

Use updated coding and follow plan prior authorization procedures

The policy's coding table was updated (including addition of 0651U); follow the plan's coding and prior authorization procedures and the updated code list when ordering tests.

Reference the updated code list (policy revision 08/01/2026) when submitting claims or authorization requests
Follow plan-specific prior authorization workflows and code requirements

Documentation Required

Offer pretest genetic counseling

Pretest genetic counseling is strongly recommended to inform individuals about the advantages, limitations, potential for VUS results, and implications for family members prior to testing.

Provide documentation that pretest counseling was offered or performed when submitting test requests
Discuss benefits, limitations, and potential outcomes including VUS and cascade testing

Documentation Required

Document testing approach (panel vs stepwise)

Select testing approach thoughtfully: multigene panels may be more efficient than stepwise single-gene testing in some families but can include low- or moderate-risk genes that increase uncertain results; document the chosen approach and rationale.

When ordering a panel, justify panel size based on family history and differential diagnosis
Consider and document why stepwise testing was not used if relevant

Step Therapy

Test an affected relative first; document prior single-gene negatives

When possible, test an affected relative first before testing an unaffected individual; if prior single-gene testing was negative but suspicion remains, document reasons for subsequent multigene testing.

Document attempts to obtain affected-relative samples or rationale if unavailable
If prior single-gene negative testing exists, include clinical justification for expanded panel testing

Documentation Required

Document rationale when choosing panels over targeted testing

Guidelines historically favored targeted analysis for the most likely syndrome; use panels when multiple syndromes are considered and document why panel testing is preferred over targeted testing.

Record clinical features that broaden the differential diagnosis requiring panel testing
Explain why targeted gene analysis would be insufficient in the specific case

Step Therapy

Use focused panels when rapid results are needed

Consider smaller, focused gene panels first when rapid results are needed for treatment decisions; larger or broader panels may be ordered subsequently and should be justified in records.

If rapid therapeutic decisions are required, order focused panel and document urgency
If ordering larger panel later, document clinical changes or additional indications supporting expansion

Step Therapy

Use stepwise DNA then RNA testing; include impact documentation for RNA

Perform DNA testing first and reserve RNA testing for selective use to clarify inconclusive splicing variants; when submitting RNA testing with DNA panels, include documentation of how RNA results alter variant classification or patient management.

Provide evidence that RNA testing is expected to resolve a specific VUS or splicing question
Document how RNA results would change clinical management if reclassification occurs

Note

Provider actions — reserved

Reserved (no provider actions listed in inventory).

Documentation Required

Include a pedigree drawing/diagram with the request

A pedigree drawing/diagram using standardized nomenclature should be included in contemporaneous medical records submitted with the testing request to document personal and family history.

Include first-, second-, and third-degree relatives with ages at diagnosis and current age or age at death
Use standardized pedigree notation per NCCN guidance

Documentation Required

Submit comprehensive family history and clinical details

Provide a detailed family history including first-, second-, and third-degree relatives, ages at diagnosis, cancer primary sites, bilateral disease, and current age or age at death to support testing necessity.

Record primary cancer sites, ages at onset, and any syndromic features
Include relevant medical and surgical history and results of physical exam

Documentation Required

Document genetic counseling discussion and sufficient history

Documentation should include evidence that genetic counseling occurred (discussion of benefits/limitations, informed consent) and sufficient personal and family history to meet guideline criteria when seeking coverage.

Attach notes indicating pretest counseling, informed consent, and discussion of VUS potential
Provide records demonstrating criteria per NCCN/ASCO were evaluated

Documentation Required

Order multigene testing with genetic expertise and document involvement

Multigene testing should be offered with professional genetic expertise, including pre- and post-test counseling; document that testing was ordered by or in conjunction with clinicians experienced in hereditary cancer genetics when applicable.

Document involvement of genetic counselor or genetics-trained clinician for complex panels
Record laboratory choice and panel composition rationale as part of the clinical record

Documentation Required

Record family history and refer to genetics for counseling when indicated

Take and record a comprehensive family history for all patients with cancer and refer to genetics professionals when needed; document counseling and plan for cascade testing if P/LP variants are found.

Note plan for facilitating cascade testing of relatives if a P/LP variant is identified
Record counseling outcomes and any referrals made

Documentation Required

When submitting RNA testing, document expected impact on variant classification/management

When RNA testing is submitted with DNA-based hereditary cancer panels, include documentation describing how the RNA results are expected to alter variant classification or patient management given limited evidence for routine concurrent use.

State the specific variant(s) or splicing concerns RNA testing will address
Explain anticipated impact on clinical decision-making if reclassification occurs

Billing Rule

Reference applicable benefit plan terms in requests

Coverage decisions reference the applicable federal, state, or contractual benefit plan terms; providers should document adherence to plan-specific coverage rules when submitting requests.

Confirm and document that testing aligns with member's benefit plan requirements
Note any state or federal mandates that may affect coverage in the submission

Documentation Required

Provide required medical records to support coverage review

Medical records documentation may be required to assess whether the member meets clinical criteria for coverage; include contemporaneous records and pedigree but understand documentation does not guarantee coverage.

Attach all supporting records used to evaluate eligibility for testing
Acknowledge that submission of records supports review but is not a coverage guarantee

Denial Risk

Risk of denial if personal/family history is not documented

Lack of documented personal or family history consistent with hereditary cancer susceptibility may lead to noncoverage; testing is generally recommended only when history supports hereditary risk, the test can be interpreted, and results will influence management.

Ensure submitted history demonstrates how testing meets medical necessity criteria
If history is limited, provide additional context or risk-model scores to support testing

Prior Authorization

Document therapy-related rationale to reduce noncoverage risk

Order BRCA1/2 and expanded gene testing when results will inform therapy decisions (for example, eligibility for PARP inhibitor therapy) or family risk; absence of such indications may increase noncoverage risk.

Document therapeutic implications (e.g., PARP inhibitor candidacy) in authorization requests
Include tumor staging or treatment plans if testing is being used to guide systemic therapy

Denial Risk

Avoid unnecessary large panels or justify broad panel composition

Be aware that ordering large, broad panels increases the likelihood of variants of uncertain significance and may include genes with limited management data; inappropriate panel selection can reduce clinical utility and may affect coverage.

Justify inclusion of low- or moderate-penetrance genes when ordering broad panels
Document expected clinical utility and management changes from identified genes

Documentation Required

Order tests with genetic counseling to avoid interpretation harms

Order testing with appropriate genetic counseling or specialist involvement; lack of genetic expertise when ordering or interpreting large multigene panels may lead to harms and could be grounds for concern if clinical utility is not demonstrated.

Document involvement of genetic counselors or genetics-trained clinicians for complex cases
Ensure pre- and post-test counseling is arranged and noted in the record

Denial Risk

PRS insufficient as sole rationale; may lead to denial

Do not submit polygenic risk scores (PRS) as the sole clinical rationale for hereditary cancer testing; evidence is insufficient and PRS may be a basis for denial when used to justify testing.

If PRS is provided, include conventional personal/family history or guideline criteria to support testing
Discuss PRS limitations with patients and document counseling

Denial Risk

Check for conflicting benefit terms that can affect coverage

Confirm that federal, state, or contractual benefit requirements applicable to the member do not conflict with the policy; conflicting benefit terms may override the policy and could trigger denial if not met.

Verify member-specific plan coverage rules and document any mandatory state/federal provisions
If conflicts exist, follow the jurisdictional or contractual requirement in the authorization request

Applicable Procedure and Billing Codes

Applicable molecular procedure codes (selected list)mixed

0138U	BRCA1 (BRCA1) and BRCA2 mRNA sequence analysis (list separately)
81162	BRCA1/BRCA2 full sequence analysis and full duplication/deletion analysis
81163	BRCA1/BRCA2 full sequence analysis
81164	BRCA1/BRCA2 full duplication/deletion analysis
0133U	Hereditary prostate cancer-related disorders, targeted mRNA sequence analysis panel (11 genes)
0134U	Hereditary pan cancer targeted mRNA sequence analysis panel (18 genes)
0162U	Hereditary colon cancer (Lynch syndrome) targeted mRNA sequence analysis panel (MLH1, MSH2, MSH6, PMS2)
0238U	Genomic DNA sequence analysis of MLH1, MSH2, MSH6, PMS2, and EPCAM including small sequence changes, deletions, duplications
81479	Unlisted molecular pathology procedure
0213U	Whole genome and mitochondrial DNA sequence analysis for rare diseases (proband/comparator genomes variants)

1–10 of 12

1/2

Applicable CPT/PLA/Unlisted codesmixed

0213U	Rare diseases (constitutional/heritable disorders), whole genome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, proband.
0214U	Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, proband.
0215U	Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, each comparator exome (e.g., parent, sibling).
0265U	Whole Exome and Whole Genome Sequencing Rare constitutional and other heritable disorders, whole genome and mitochondrial DNA sequence analysis, blood, frozen and formalin-fixed paraffin-embedded (FFPE) tissue, saliva, buccal swabs or cell lines, identification of single nucleotide and copy number variants.
0266U	Whole Exome and Whole Genome Sequencing Rare constitutional and other heritable disorders, whole genome and mitochondrial DNA sequence analysis, blood, frozen and formalin-fixed paraffin-embedded (FFPE) tissue, saliva, buccal swabs or cell lines, identification of single nucleotide and copy number variants (comparator genomes).
81416	Exome; sequence analysis, each comparator exome (List separately in addition to code for primary procedure).
81417	Exome; re-evaluation of previously obtained exome sequence (e.g., updated knowledge or unrelated condition/syndrome).
81425	Genome; sequence analysis.
81426	Genome; sequence analysis, each comparator genome (List separately in addition to code for primary procedure).
81427	Genome; re-evaluation of previously obtained genome sequence (e.g., updated knowledge or unrelated condition/syndrome).

1–10 of 11

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Updated applicable CPT/HCPCS codesCPT

0651U

Supporting information — newly added code listed in policy update

inv-29: Risk model thresholds

Tyrer-Cuzick / BRCAPRO / CanRisk (personal history)Score ≥ 2.5% for BRCA1/2 pathogenic variant

Tyrer-Cuzick / BRCAPRO / CanRisk (no personal history)Score ≥ 5% for BRCA1/2 pathogenic variant

PREMM5 / MMRpro / MMRpredict (personal history)Score ≥ 2.5% for having a Lynch syndrome gene mutation

PREMM5 / MMRpro / MMRpredict (no personal history)Score ≥ 5% for having a Lynch syndrome gene mutation

inv-30: Policy revision date

Policy revision (effective) date08/01/2026

Policy history noteUpdated applicable CPT codes and added 0651U; prior version CS049.AA archived

Tests and Indications Not Covered

RNA panel testing, PRS, and WES/Exome+ are listed among tests considered unproven or not medically necessary for routine hereditary cancer identification. RNA panels may have selective utility for clarifying specific variants, PRS lacks sufficient evidence to guide management, and Exome+/WES can find additional carriers in population screening but raises implementation and interpretation challenges; these points are summarized in the policy's not-covered and evidence-consideration sections.

Routine population-based multigene panel testing without clinical indications is not covered. The policy cautions that panels used in unselected populations often include genes with weak or unclear gene–disease associations and can generate findings that are not actionable, leading to potential unnecessary interventions.

Routine population screening genetic testing (including routine BRCA testing) for individuals without a personal or family history or relevant ancestry is not supported. The USPSTF guidance cited in the policy recommends targeted screening and testing based on screening tool results and family-history assessment rather than universal testing.

Multisyndrome panels intended for indications where evidence is minimal or guidelines are unclear are not covered as routine options. The policy references a Hayes report and reviews that found limited or unclear support for broad multisyndrome panel testing in certain contexts.

Polygenic risk scores for hereditary cancer risk assessment are not covered for routine clinical use due to insufficient evidence. The policy states PRS are investigational for this purpose and should not guide standard hereditary cancer management.

Routine clinical implementation of PRS is not supported by the current evidence base and therefore is not covered as a standard clinical service; clinicians proposing PRS-based management should document justification and verify benefit plan terms.

Routine concomitant RNA panel testing for all hereditary cancer panel submissions is not covered as standard practice. The policy favors selective, stepwise RNA testing performed to clarify specific DNA-identified splicing variants rather than universal concurrent RNA panels.

The policy does not list an exhaustive set of individual tests as universally not covered; specific coverage determinations depend on the member's plan benefit terms and applicable federal or state requirements. Providers should consult benefit plan language when submitting requests.

Background and Evidence Summary

Hereditary cancer syndromes account for a minority of cancers but confer substantially increased lifetime risk for particular tumor types; the policy frames MGPT as a tool to identify pathogenic/likely pathogenic variants that can alter surveillance, treatment, and cascade testing for family members. The background emphasizes the need for detailed family history and selective testing guided by clinical criteria and guidelines.

5+Policy definition: minimum genes for a Multigene Panel

13%PGV prevalence in unselected solid tumor MGPT cohort (Samadder et al.)

14.2%Patients with ≥1 P/LP variant in CRC MGPT cohort (Coughlin et al.)

0651UNew CPT/HCPCS code added in policy update

inv-61: Definition: Multigene Panel (5+ genes)

DefinitionGenetic tests that use next-generation sequencing to test multiple genes simultaneously; for this policy, a Multigene Panel consists of five or more genes.

SynonymsMultigene test; multiple-gene panel test; MGPT

Typical useSimultaneous sequencing of hereditary cancer susceptibility genes to detect pathogenic/likely pathogenic variants and variants of uncertain significance (VUS).

inv-64: MGPT definition and scope — simultaneous sequencing to detect P/LP variants

MGPT is defined for the purposes of this policy as simultaneous sequencing of multiple hereditary cancer susceptibility genes to detect pathogenic or likely pathogenic variants:

MGPT definition: Multigene panel testing (MGPT) refers to simultaneous sequencing of multiple hereditary cancer susceptibility genes (policy defines a multigene panel as testing five or more genes) to detect pathogenic/likely pathogenic variants and variants of uncertain significance.

Policy definition and scope

The policy cites empirical evidence and guideline summaries (ASCO, NCCN and related studies) to inform coverage considerations: ASCO and NCCN recommend comprehensive family-history collection and offering MGPT when indicated by history or when results may affect treatment; cohort studies show variable yields of clinically actionable variants depending on cancer type and panel composition. These evidence nodes underpin the policy stance that MGPT is appropriate when clinical criteria are met, while broader population screening and some adjunct tests remain unproven.

Guideline summaries referenced in the policy (ASCO, NCCN) recommend taking a comprehensive family history, ensuring genetic expertise when ordering MGPT, including strongly recommended genes for the cancer type on panels, and offering germline testing when results could influence treatment, clinical trial eligibility, or family risk. These guideline-based recommendations inform appropriate test selection and eligibility assessments.

Evidence-informed coverage considerations in the policy balance MGPT's demonstrated diagnostic yield in certain cancer cohorts against risks of uncertain findings from large panels. Studies cited show meaningful detection rates in CRC, pancreatic, and unselected solid tumor cohorts, while RNA testing and PRS are noted as having limited or preliminary supporting data; WES/Exome+ may identify additional carriers but raises implementation and equity concerns.

Definitions and Terminology

inv-60: Definition — BRCA-Related Cancers (list)

BRCA-related cancers (list)Breast cancer; Ovarian cancer (including fallopian tube and primary peritoneal); Pancreatic adenocarcinoma; Prostate cancer

Source guidanceNCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate v1.2026

inv-61: Definition — Multigene Panel

Multigene Panel (policy definition)Genetic tests using NGS to test multiple genes simultaneously; for this policy, consists of five or more genes.

Also calledMultigene test; multiple-gene panel test

inv-62: Definition — Limited Family History

Limited Family HistoryFewer than two known first-degree or second-degree female relatives surviving beyond 45 years of age on either or both sides of the family (e.g., adoption).

ImplicationMay limit applicability of family-history–based testing criteria

inv-63: Definition — Hereditary cancer susceptibility testing

Hereditary cancer susceptibility testing — definitionGenetic testing used to predict an individual's risk of developing cancer by identifying germline variants associated with increased cancer risk.

Clinical purposeInform diagnosis, medical management of the individual, and cascade testing of at-risk family members

inv-64: Definition — MGPT (abbreviation)

MGPT (abbreviation)Multigene panel testing — simultaneous sequencing of multiple hereditary cancer susceptibility genes to detect P/LP variants and VUS.

Typical panel sizeVaries by indication; policy defines multigene panel as ≥5 genes and many published panels include 10–50+ genes.

inv-65: Definition — P/LP (pathogenic/likely pathogenic)

P/LPPathogenic or likely pathogenic variants associated with increased cancer risk

Clinical actionP/LP findings can guide surveillance, risk-reducing interventions, treatment decisions, and cascade testing

inv-66: Definition — Lynch syndrome

Lynch syndrome — definitionPresence of germline heterozygous pathogenic/likely pathogenic variants in MMR genes (MLH1, MSH2, MSH6, PMS2) or 3' terminal deletions of EPCAM; associated with increased risks for colorectal, endometrial, and other cancers.

Associated genesMLH1, MSH2, MSH6, PMS2, EPCAM

inv-67: Definition — dMMR

dMMR — definitionTumor mismatch repair deficiency identified by microsatellite instability high or abnormal MMR protein expression on immunohistochemistry (loss of MLH1, MSH2, MSH6, or PMS2).

ImplicationTumor dMMR may prompt germline testing for Lynch syndrome genes

inv-68: Definition — Polygenic risk score (PRS)

Polygenic risk score (PRS) — definitionAn evaluation of risk based on the combined effect of many genetic variants; may include variants with or without known gene associations.

Policy stanceEvidence is currently insufficient to support PRS for hereditary cancer risk assessment as a routine clinical test.

inv-69: Definition — PRS (abbreviation)

PRS (abbreviation)Polygenic Risk Score

NoteIncludes combined-effect scoring from many genetic variants; policy cites insufficient evidence for routine clinical use.

inv-70: Definition — RNA testing (concurrent)

RNA testing (concurrent) — definitionRNA sequencing/panel analysis performed at the same time as DNA-based hereditary cancer panel testing to detect splicing effects and clarify variant interpretation.

Policy noteConcurrent RNA panel testing lacks sufficient high-quality evidence for routine use; may clarify some variants after DNA testing.

inv-71: Definition — Exome+/WES

Exome+ / WES — definitionWhole-exome sequencing or enhanced exome platforms used for germline screening of hereditary cancer predisposition genes (Exome+ used in large-scale screening studies).

Policy cautionExome+/WES can identify additional carriers not meeting guideline criteria but has limitations (CNV detection, population representation); broader adoption requires further study.

inv-72: Definition — multigene panel test referenced to NCI and literature

Multigene panel test — referenceDefined and referenced via the NCI Dictionary of Genetics Terms and cited literature discussing panels of cancer predisposition genes (NCI definition).

ContextPolicy references published studies and NCI definition when describing panel composition and use.

inv-73: Definition — polygenic risk score referenced to NCI

Polygenic risk score — referenceReferenced via NCI Dictionary of Genetics Terms; defined as combined-effect risk evaluation from many variants.

Policy interpretationPolicy cites NCI definition and states evidence for clinical use in hereditary cancer is insufficient.

Policy Revision History

2026-08-01operational updateLatest

Updated applicable CPT/HCPCS coding table to reflect quarterly edits and added code 0651U; supporting information from prior policy version CS049.AA archived.

This policy revision updated the applicable procedure code list to reflect quarterly coding edits and added code 0651U. Providers should reference the updated coding and prior authorization procedures when submitting requests.