CurrentUnitedHealthcarePolicy MMP383.24

Molecular Pathology/Genetic Testing Reported with Unlisted Codes

Policy governs when molecular pathology and genetic testing services reported with unlisted codes (including CPT 81479) are considered reasonable and necessary for Medicare Advantage members and related commercial lines. It defines clinical criteria for many named assays, NGS/CGP/targeted panels, pharmacogenomics, MRD, liquid biopsy, and other molecular tests and references CMS NCD/LCD compliance.

Policy Summary

PayerUnitedHealthcare

PolicyMolecular Pathology/Genetic Testing Reported with Unlisted Codes

Policy CodePolicy MMP383.24

Change TypeAdditions, removals, and revisions to CPT 81479 indications and associated ICD-10 codes

Effective DateJun 1, 2025

Next Review Date

Key ActionWhen reporting laboratory tests with an unlisted code, include the specific name of the laboratory test(s) and/or a short descriptor of the test(s) in documentation and claim submission.

POLICY UPDATE CHANGES

Effective date June 1, 2025 with last committee approval May 14, 2025; policy outlines use of CPT 81479 and specific clinical criteria for various molecular tests.

Revised list of covered tests; added biomarkers for CPT 81479 (Biomarkers for Oncology).

Removed language indicating PathfinderTG® is reasonable and necessary as occasional second-line supplement.

Added PancraGEN® (Powered by PathfinderTG) to Non-Covered Indications for CPT Code 81479.

Modified content headings and associated ICD-10 diagnosis codes for multiple CPT 81479 groupings (ClonoSEQ®, Guardant360®, NGS testing).

Updated Clinical Evidence and References sections.

Removed outdated CMS transmittal reference links.

Coverage Summary & Scope

This policy (UnitedHealthcare Medicare Advantage Medical Policy No. MMP383.24, effective June 1, 2025, last committee approval May 14, 2025) governs molecular pathology and genetic testing services reported with unlisted procedure codes—primarily CPT 81479. It interprets CMS guidance including NCD 90.2 and references applicable LCDs/LRAs for MolDX and other Medicare contractors. Scope includes comprehensive genomic profiling (CGP), targeted NGS panels (including small 2–4 gene panels), plasma-based assays (liquid biopsy/ctDNA), MRD testing, pharmacogenomics (PGx), named assays, and other molecular diagnostics. The policy establishes clinical, analytical, and technical assessment requirements (analytic validity, clinical validity, and clinical utility) and operational coding guidance for use of unlisted codes when no specific CPT exists, and it lists named tests that are covered, limited, or non-covered (for example, PancraGEN®/PathfinderTG® moved to non-covered).

Policy summary — key facts

Policy NumberMMP383.24

Effective DateJune 1, 2025

Last Review / Committee ApprovalMay 14, 2025

PayerUnitedHealthcare

Primary CPT impacted81479 (Unlisted molecular pathology procedure)

Primary scopePolicy governs when molecular pathology and genetic testing services reported with unlisted codes (including CPT 81479) are reasonable and necessary, defines clinical criteria for named assays, NGS/CGP/targeted panels, pharmacogenomics, MRD, liquid biopsy, and references CMS NCD/LCD compliance.

Part 1 of 9 summarizes coding and coverage updates for services reported with CPT 81479, including additions and removals to 81479 groupings, named tests added to non-covered lists (for example, PancraGEN® / PathfinderTG® moved to non-covered), and modifications to ICD‑10 diagnosis code groupings associated with 81479 content groups. This part focuses on operational coding guidance and clinical criteria; the policy indicates that material changes affecting coverage positions are included across the document and identifies that there has been material change in certain test listings and code groupings effective 06/01/2025.

Medical Necessity: Criteria and Decision Trees

General principles for unlisted molecular pathology services

General principles for unlisted molecular pathology services. Use CPT 81479 (or other unlisted molecular pathology code) only when no specific code adequately describes the service. When an unlisted code is reported, include the test name, method, genes or analytes interrogated, specimen type, and rationale in the medical record and claim documentation.

Unlisted molecular pathology services are reasonable and necessary when all of the following are met:

- No specific CPT/HCPCS code accurately describes the laboratory procedure performed.

- The test is ordered by a qualified clinician and is expected to provide information that will affect clinical management (diagnosis, prognosis, or treatment selection).

- The laboratory provides a clear, itemized report including methods, genes/variants analyzed, analytical validity (limits of detection, assay sensitivity/specificity when available), and the bioinformatic/variant interpretation workflow.

Not Medically Necessary / Tests with Insufficient Evidence

Overall clinical-evidence conclusions for tests discussed in this part

Summary conclusions based on reviewed studies and methodological limitations (overall clinical-evidence conclusions):

Insufficient evidence for many tests: For multiple individual molecular pathology lab tests reported with unlisted codes, the clinical evidence is insufficient to conclude these tests impact therapeutic decision-making or directly affect treatment/outcomes for the Medicare population.
Specific insufficient tests examples: Specific tests with insufficient evidence include BluePrint, 40-GEP for cSCC, HAX1, HTTLPR, KIF6, LPA-Intron 25, PancraGEN®, Prometheus IBD sgi, SULT4A1, VEGFR2 (see non-covered list).
dd-cfDNA promising but needs more study: Donor-derived cell-free DNA (dd-cfDNA) assays show promising diagnostic performance for detecting organ allograft rejection (examples: kidney, heart, lung) but further studies are needed; reported thresholds (eg, 1.0%) and performance metrics exist in individual studies.

Coding Guidance & Referenced Billing Documents

Unlisted molecular pathology code for services not otherwise describedCPTCovered

81479

Unlisted molecular pathology procedure (used for CGP, small targeted panels 2-4 genes, NGS not otherwise described, BCR-ABL multiple tests assigned a single ID, and when no specific CPT exists)

NGS/CGP - reporting notemixedCovered

multiple

Targeted NGS panels with specific CPT codes exist for many panels; CGP and other tests not described should use 81479; CGP coverage limited to one test per surgical specimen.

Unlisted procedure / reference codes (applicable codes listed for reference)CPT|mixed

81479	Unlisted molecular pathology procedure.
81599	Unlisted multianalyte assay with algorithmic analysis.
84999	Unlisted chemistry procedure

Non-covered tests reported with CPT 81479mixedNot Covered

	BluePrint® test
	Molecular biomarker testing for risk stratification of cutaneous squamous cell carcinoma
	HAX1 gene sequencing and panels of tests that include the HAX1 gene
	Serotonin transporter genotyping (HTTLPR)/ HTTLPR gene testing
	KIF6 genotype test
	LPA-Intron 25 genotype test
	Prometheus IBD sgi diagnostic test
	SULT4A1 genetic testing and panels of tests that include the SULT4A1 gene
	VEGFR2 testing and panels of tests that include the VEGFR2 receptor
	PancraGEN® (Powered by Pathfinder TG)

Referenced LCDs / Billing and Coding documents (MolDX and others)mixed

L38294	MolDX: Pharmacogenomics Testing (Noridian)
A58318	Billing and Coding: MolDX: Pharmacogenomics Testing
L38435	MolDX: Pharmacogenomics Testing (WPS)
A58395	Billing and Coding: MolDX: Pharmacogenomics Testing
L39073	Pharmacogenomics Testing (First Coast)
A58812	Billing and Coding: Pharmacogenomics Testing
L39063	Pharmacogenomics Testing (Novitas)
A58801	Billing and Coding: Pharmacogenomics Testing
L38584	MolDX: Phenotypic Biomarker Detection from Circulating Tumor Cells (CGS)
A58063	Billing and Coding: Phenotypic Biomarker Detection from CTCs

1–10 of 73

1/8

No procedure or billing codes provided in this sectionmixed

No codes listed

Affected CPT codeCPT

81479

Unlisted molecular pathology/genetic testing (used as reporting code for multiple biomarkers/tests described)

Added/Modified ICD-10 diagnosis codes associated with CPT 81479 (ClonoSEQ®)ICD-10

C83.1A	Mantle cell lymphoma, initial encounter (added)
Z85.72	Personal history of other malignant neoplasm of lymphoid, hematopoietic and related tissue (added)

Added/Modified ICD-10 diagnosis codes associated with CPT 81479 (Guardant360®)ICD-10

C70.0	Malignant neoplasm of meninges (added)
C80.2	Secondary malignant neoplasm of other specified sites (added)

Added/Modified ICD-10 diagnosis codes associated with CPT 81479 (NGS testing for myeloid malignancies)ICD-10

D75.821

Clonal cytopenia / added diagnosis code (D75.821 added)

Biomarkers explicitly mentioned as Added/Removed in Summarymixed

SDHB	Biomarker listed as added
SDHC	Biomarker listed as added
SDHD	Biomarker listed as added
VHL	Biomarker listed as added
TSC2	Previously in heading; referenced

Operational coding clarifications: CPT 81479 is appropriate when no specific CPT code adequately describes the molecular pathology service (including CGP, small targeted panels of 2–4 genes, or NGS tests not otherwise described). When using an unlisted code, the specific test name and/or a short descriptor must be included on the claim and supporting documentation. Coverage of CGP is limited to one test per surgical specimen and precludes other molecular testing on that specimen. For jurisdictional coverage of tests such as PancraGEN®, providers must cross-reference applicable MAC/LCDs (e.g., L39365, L39367) and follow contractor guidance where required.

Provider Actions: Documentation, Prior Authorization & Billing Rules

Documentation Required

Document test details when using unlisted code

When reporting a laboratory test using an unlisted code (for example CPT 81479), include the specific test name and/or a concise descriptor of the methodology or target so the service can be adjudicated. This documentation requirement supports medical necessity review, clinical validation assessment, and any downstream prior authorization or coding verification.

Affected code: CPT 81479

Prior Authorization

Technical assessment requirement

Tests reported with unlisted codes that are not otherwise supported by an established prior authorization pathway may require a technical assessment. Laboratories and ordering clinicians should document analytic validity (AV), clinical validity (CV), and clinical utility (CU) of the assay and indicate the intended patient population and clinical indication for use.

Background, Definitions & Evidence Highlights

Background: This UnitedHealthcare Medicare Advantage policy interprets CMS guidance (including NCD 90.2) and defines clinical, analytic, and utility evidence and technical assessment requirements for molecular diagnostics. It provides named‑test coverage positions and operational coding guidance emphasizing appropriate use of CPT 81479 when no specific CPT exists. Part 1 of 9 specifically addresses named-test coverage positions and coding/operational guidance for services reported with unlisted molecular pathology codes.

Term	Definition
{"text":"CGP","status":""},{"text":"Comprehensive Genomic Profile: NGS-based assay providing broad genomic characterization beyond hotspot panels; not currently described by existing CPT codes; reported with CPT 81479.","status":""}
{"text":"Targeted NGS panel","status":""},{"text":"Panels identifying somatic alterations in certain hotspot regions; may have specific CPT codes depending on gene content; small panels (2-4 genes) use 81479 per policy.","status":""}
{"text":"MyPRS","status":""},{"text":"Microarray-based GEP assay of a 70-gene signature (GEP70) on CD138+ plasma cells from bone marrow aspirate generating 0-100 risk score; cutoff 45.2.","status":""}
{"text":"MolDX","status":""},{"text":"Molecular diagnostics program used by Medicare MACs (Palmetto MolDX) for coverage and coding determinations.","status":""}
{"text":"S-LAM","status":""},{"text":"Sporadic lymphangioleiomyomatosis.","status":""}
{"text":"ctDNA","status":""},{"text":"Circulating tumor DNA — tumor-derived fragmented DNA in plasma used for detection of mutations and MRD.","status":""}
{"text":"MRD","status":""},{"text":"Minimal (measurable) residual disease — molecular evidence of residual cancer after treatment.","status":""}
{"text":"GEP","status":""},{"text":"Gene expression profiling — assays measuring expression patterns to prognosticate or predict outcomes (eg, MammaPrint, 31-GEP).","status":""}
{"text":"Percepta GSC","status":""},{"text":"A genomic sequencing classifier applied to bronchial-airway samples to re-classify risk of pulmonary nodules after nondiagnostic bronchoscopy.","status":""}
{"text":"CTC","status":""},{"text":"Circulating tumor cell; tumor cells detected in blood used for phenotypic or molecular biomarker analysis.","status":""}
{"text":"AR-V7","status":""},{"text":"Androgen receptor splice variant 7 detected in CTCs, associated with resistance to AR-targeted therapies in mCRPC.","status":""}
{"text":"PGx","status":""},{"text":"Pharmacogenomics — genetic testing to guide drug selection and dosing.","status":""}
{"text":"dd-cfDNA","status":""},{"text":"Donor-derived cell-free DNA measured in recipient plasma as a biomarker for allograft injury/rejection.","status":""}
{"text":"ProMark","status":""},{"text":"An 8-biomarker tissue-based proteomic assay producing a risk score for prostate cancer pathology.","status":""}
{"text":"40-GEP","status":""},{"text":"40-gene expression profile test for risk stratification of cutaneous squamous cell carcinoma.","status":""}
{"text":"IMP / PancraGEN","status":""},{"text":"Integrated molecular pathology test (PancraGEN by Interpace Diagnostics) intended to assess malignant potential of pancreatic cysts (not covered / insufficient evidence per policy).","status":""}

Selected evidence highlights: clonoSEQ analytical performance showed a limit of detection (LoD) of 1.903 cells, limit of quantitation (LoQ) of 2.390 cells, and precision ranging with CVs reported in validation studies. ctDNA/dd‑cfDNA studies reported diagnostic thresholds and performance metrics—dd‑cfDNA cutoff of 1.0% in renal transplant DART study had PPV 61% and NPV 84% for active rejection and an AUC of 0.87; a lung transplant study reported dd‑cfDNA ≥ 1.0% with sensitivity 73.9% and specificity 87.7% for acute lung allograft dysfunction. Percepta GSC real‑world registry data down‑classified risk in 34.3% of cases and down‑classification led to management changes to surveillance in ~74% of those down‑classified; Percepta down‑classification could reduce invasive procedures by ~50% in prospective study cohorts. Guardant360® plasma profiling changed treatment in 32% of patients with insufficient tissue (Rozenblum et al.), and addition of plasma testing increased patients eligible for targeted therapy from 21% to 36% in Aggarwal et al. AlphaLiquid100 ctDNA assay in real‑world NSCLC detected actionable mutations in 60.7% (74/122) with PPA against tissue NGS of 85.3% overall and high PPA for EGFR (~95.7%). MSK-IMPACT and other comprehensive NGS efforts identified that a large share of mutations are outside hotspot panels (MSK-IMPACT reported ~81% of mutations outside combined hotspot regions and ~69% not previously in COSMIC), supporting more comprehensive NGS approaches for detection of actionable alterations.

Medicare NCDs & LCDs Referenced

Name	Number	Type	Effective Date
{"text":"Next Generation Sequencing","status":""},{"text":"90.2","status":""},{"text":"NCD","status":""},{"text":"","status":""}
{"text":"Genetic Testing in Oncology: Specific Tests","status":""},{"text":"L39365 / L39367","status":""},{"text":"LCD","status":""},{"text":"2025-04-24","status":""}
{"text":"MolDX: Gene Expression Profile Tests for Decision-Making in Castration Resistant and Metastatic Prostate Cancers","status":""},{"text":"L39648","status":""},{"text":"LCD","status":""},{"text":"2024-09-22","status":""}
{"text":"MolDX: Molecular Testing for Risk Stratification of Thyroid Nodules","status":""},{"text":"L39650 / L39682 / L39684","status":""},{"text":"LCD","status":""},{"text":"2024-07-28","status":""}
{"text":"MolDX: Molecular Diagnostic Tests and various MolDX LCDs","status":""},{"text":"multiple (see code_groups)","status":""},{"text":"LCD","status":""},{"text":"","status":""}
{"text":"Genetic Testing in Oncology: Specific Tests","status":""},{"text":"L39365 / L39367","status":""},{"text":"LCD","status":""},{"text":"2025-04-24","status":""}

Revision History & Policy Changes

2025-06-01clarifiedLatest

Effective date June 1, 2025 with last committee approval May 14, 2025; policy outlines use of CPT 81479 and specific clinical criteria for various molecular tests.

2025-06-01revisedLatest

Revised list of covered tests; added biomarkers for CPT 81479 (Biomarkers for Oncology) and modified content headings for CPT 81479 groupings.

2025-06-01removed

Policy Summary

PayerUnitedHealthcare

PolicyMolecular Pathology/Genetic Testing Reported with Unlisted Codes

Policy CodePolicy MMP383.24

Change TypeAdditions, removals, and revisions to CPT 81479 indications and associated ICD-10 codes

Effective DateJun 1, 2025

Next Review Date

Key ActionWhen reporting laboratory tests with an unlisted code, include the specific name of the laboratory test(s) and/or a short descriptor of the test(s) in documentation and claim submission.

On This Page

CMS NCD 90.2 Next Generation Sequencing (NGS) requirement

CMS National Coverage Determination (NCD) 90.2 for Next Generation Sequencing (NGS) applies where Medicare members meet NCD criteria. When NCD 90.2 applies, tests and laboratories must meet NCD-specified requirements.

NCD applicability:

- Medicare members only: when testing is performed to inform treatment selection in patients with advanced solid tumors (per NCD 90.2).

- The NCD requires FDA-cleared/approved tests or NGS tests performed in CLIA-certified laboratories that meet the NCD’s stated analytic and clinical validity and that are used to guide cancer treatment with an FDA-approved drug or cancer clinical trial.

NCD-specific criteria (apply all):

- Test is performed in a CLIA-certified laboratory.

- Test is either FDA-approved/cleared for the intended use or meets the NCD’s evidentiary and technical requirements for laboratory-developed tests.

- Test results will be used to inform treatment selection with an FDA-approved indication or to enroll the patient in a qualifying clinical trial.

- The report includes genes and variants with clinical interpretation and therapeutic implications per NCD definitions.

- Documentation that the patient has advanced/metastatic disease as defined by the NCD and that results will affect management.

Use of CPT 81479

Appropriate uses for CPT 81479 (Unlisted molecular pathology procedure). 81479 may be used in defined, limited situations when no specific code exists.

Any of the following uses for CPT 81479 are appropriate:

- Reporting multiple BCR-ABL breakpoint analyses (major, minor, other) when a single specific CPT does not describe the full set of tests performed.

- Reporting BCR-ABL translocation analysis performed by NGS when no specific CPT for that NGS translocation analysis is available.

- Reporting a small, targeted single-gene or few-gene laboratory-developed test (LDT) where CPT codes for individual analytes are not available and the test is clinically indicated.

- Reporting clinically-directed custom or add-on analyses to previously coded testing panels when the new analytic content has no specific CPT code.

- Reporting multi-analyte NGS assays (not covered by existing panel codes) where a single unlisted code is required because no specific CPT describes the assay.

Operational note: When 81479 is used, provide detailed documentation of test content, method, genes/variants interrogated, and clinical rationale to support medical necessity.

Guardant360® (plasma-based genomic profiling) coverage

Coverage criteria for Guardant360® plasma-based genomic profiling (liquid biopsy). Guardant360® is reasonable and necessary only when all listed conditions are met, including the nested condition about intent to pursue further cancer treatment.

ALL of the following

Patient has a recurrent, relapsed, refractory, metastatic, or advanced solid tumor that did not originate from the central nervous system. (Patients meeting indications on the FDA larotrectinib label for NTRK mutation may be considered advanced).
Patient has not previously been tested with Guardant360® for the same genetic content, unless there is clinical evidence of tumor evolution warranting retesting for different genetic content.
Patient is untreated for the cancer being tested, or is not responding to treatment (progression or new lesions).
Tissue-based comprehensive genomic profiling (CGP) is infeasible (quantity not sufficient, biopsy medically contraindicated) or—specifically for NSCLC—tissue CGP has shown no actionable mutations.
Patient intends further cancer treatment and:
- Patient is a candidate for further treatment with an FDA‑approved drug for that cancer, or a regimen with NCCN 1 or 2A recommendation for that cancer; and
- The FDA-approved indication or NCCN recommendation is based on the presence or absence of a genetic biomarker tested for in the Guardant360® assay.

InVisionFirst™ Lung (liquid biopsy) coverage for NSCLC

Coverage criteria for InVisionFirst™ Lung (liquid biopsy) in NSCLC. Meets criteria when any of the listed clinical scenarios apply and tissue-based CGP is infeasible or unavailable.

Any of the following:

- At diagnosis where results for EGFR SNVs/indels, ALK and ROS1 rearrangements, and BRAF SNVs are not available, and tissue-based CGP is infeasible (quantity not sufficient or invasive biopsy contraindicated).

- At progression for patients progressing on or after chemotherapy or immunotherapy who have not been tested for EGFR SNVs/indels, ALK and ROS1 rearrangements, and BRAF SNVs, and for whom tissue-based CGP is infeasible.

- For patients progressing on EGFR tyrosine kinase inhibitors (TKIs).

Operational note: If ctDNA is not detected or insufficient, tissue-based genotyping should be considered.

Germline testing for PARP inhibitor use

Germline testing to determine eligibility for PARP inhibitor therapy. Germline testing for BRCA1/2 (and other HRR genes where indicated) is reasonable and necessary when all conditions below are met.

All of the following:

- Patient meets clinical indication for immediate use of a PARP inhibitor for an FDA‑approved use (per therapeutic labeling and guideline recommendations).

- Patient has had no previous germline testing for hereditary cancer that included the necessary genes, and there has been no somatic tumor test of the same cancer that included those genes required for PARP indication determination.

- Patient does not meet alternative germline testing requirements per existing guidelines that would mandate more comprehensive testing instead of targeted germline testing.

Operational note: In rare circumstances limited gene testing may be acceptable when sufficient to determine PARP inhibitor eligibility and broader panel testing is not indicated per guidelines.

MRD (Minimal Residual Disease) testing

Minimal Residual Disease (MRD) testing using validated, clinically‑useful assays. MRD testing by NGS or other validated methods is reasonable and necessary when all conditions below are satisfied.

All of the following:

- MRD testing is used in a clinical context where results have established management impact (e.g., guiding adjuvant therapy decisions or surveillance strategies) per disease‑specific guidelines.

- The assay has documented analytical validity for the intended specimen and disease setting (limit of detection, sensitivity/specificity) and has clinical validation evidence supporting its prognostic or predictive use.

- When an NGS‑based multi‑analyte MRD assay is used and no specific CPT exists, CPT 81479 may be used to report the service; documentation must include assay design, genes/variants monitored, and performance characteristics.

- Frequency of MRD testing must be consistent with guideline‑recommended intervals or with evidence supporting the testing cadence.

Molecular assays for diagnosis of cutaneous melanoma

Molecular assays to aid diagnosis of cutaneous melanoma (dermatopathologist‑ordered). These tests are reasonable and necessary only when all criteria below are met.

All of the following:

- The test is ordered by the dermatopathologist reviewing the lesion and is intended to resolve histopathologic uncertainty in a lesion where morphologic evaluation alone is inconclusive.

- Specimen adequacy: formalin‑fixed paraffin‑embedded tissue from the index lesion is available and sufficient for testing; the test is not a substitute for inadequate sampling.

- The laboratory documents analytic validity (assay performance) and clinical validity for melanoma diagnosis or classification; the method is validated for the specimen type and intended diagnostic claim.

- Results are expected to change clinical management (e.g., surveillance, excision margins, or staging decisions).

MSI‑H/dMMR testing for unresectable or metastatic solid tumors (for pembrolizumab/Keytruda)

MSI‑H/dMMR testing to identify patients with unresectable or metastatic solid tumors who may benefit from pembrolizumab (Keytruda) or other immune checkpoint inhibitors. Allowed methodologies and testing limitations are provided; NGS concordance thresholds are required where noted.

All of the following for coverage:

- MSI‑H/dMMR testing is indicated for patients with unresectable or metastatic solid tumors when results would inform immunotherapy selection (e.g., pembrolizumab).

- Allowed methodologies (any one): PCR‑based MSI panels, immunohistochemistry for MMR proteins (MLH1, MSH2, MSH6, PMS2), or NGS‑based assays validated to measure MSI/dMMR.

- When using NGS for MSI/dMMR determination, the NGS method must demonstrate concordance with a validated/reference MSI method of >=95% where published or available.

- Testing must be performed on an adequate tumor specimen and reported with interpretation relevant to treatment selection.

Not covered (all):

- MSI‑H/dMMR testing is not reasonable and necessary for routine screening in early‑stage resectable tumors where results would not alter immediate therapeutic decisions.

- MSI‑H/dMMR testing without adequate analytic/clinical validation or performed on inadequate specimens is not covered.

Melanoma risk stratification molecular testing

Molecular testing for melanoma risk stratification to inform sentinel lymph node biopsy (SLNB) and other management decisions. Tests are reasonable and necessary only when all listed conditions are met.

All of the following:

- Test is ordered for primary cutaneous melanoma where conventional clinicopathologic features alone result in uncertainty regarding SLNB candidacy.

- The test is applied to the index lesion and validated to provide prognostic information that integrates with clinicopathologic risk assessment.

- Use is intended to inform recommendation for SLNB when estimated risk of SLNB‑positivity crosses the policy threshold.

- Threshold: use for SLNB decision-making when the calculated risk of sentinel lymph node positivity is >5% (threshold for consideration).

- Laboratory provides documentation of analytic and clinical validation for the test population and clear interpretation guidance tied to management recommendations.

Molecular biomarkers for risk stratification of indeterminate pulmonary nodules after non-diagnostic bronchoscopy

Molecular biomarkers for risk stratification of indeterminate pulmonary nodules after a nondiagnostic bronchoscopy. Biomarker testing is reasonable and necessary only when all criteria below are met and exclusions do not apply.

All of the following:

- Patient has an indeterminate pulmonary nodule evaluated by bronchoscopy that was nondiagnostic and conventional clinical/radiographic assessment remains indeterminate for malignancy.

- Test result would alter management (decision for surveillance vs surgical or percutaneous biopsy or definitive therapy).

- Tissue‑based sampling is infeasible or nondiagnostic and biomarker testing is intended to reduce unnecessary invasive procedures.

Exclusions (any):

- Biomarker testing is not indicated if there is a prior or current diagnosis of lung cancer that would confound interpretation.

- Not indicated for patients with recent (<5 years) history of treated lung cancer where biomarker result cannot distinguish recurrence from new primary without additional context.

- Not indicated when noninvasive imaging or clinical assessment already provides sufficient certainty to guide management.

Pharmacogenomics (PGx) testing

Pharmacogenomics (PGx) testing to guide medication selection or dosing. PGx testing (single gene or multi‑gene panels) is reasonable and necessary when all criteria are met and test selection follows the panel vs single‑gene rules below.

All of the following general requirements:

- The medication for which PGx guidance is sought is currently under active consideration for the patient (prospective use), or a clinical scenario exists where PGx results will affect immediate medication choice or dosing (reactive use).

- Test result will be used by the prescribing clinician to change drug selection, dosing, or monitoring consistent with evidence‑based guidelines (e.g., CPIC, FDA labeling, or other accepted guidance).

- The laboratory documents analytic validity and the relationship between genotypes and drug response phenotypes for the genes reported.

Panel versus single‑gene rules (all):

- Multi‑gene PGx panels are reasonable when there is a documented plan to use results to guide therapy for at least one medication whose dosing or selection is influenced by genes on the panel, or when multiple medications under consideration are guided by different genes included in the panel.

- Single‑gene testing is reasonable when a single specific gene test is clearly indicated for the medication being considered and when panel testing would provide no additional clinically actionable information.

Operational note: Some genes commonly used in PGx practice lack dedicated CPT codes; capture these in the laboratory report and billing documentation and include the clinical interpretation for the prescribing decision.

Phenotypic biomarker detection from circulating tumor cells (CTCs)

Phenotypic biomarker detection from circulating tumor cells (CTCs) for predictive or prognostic use. CTC phenotypic assays are reasonable and necessary only when all conditions below are satisfied and tissue testing is infeasible.

All of the following:

- The assay demonstrates analytic validity and clinical validity for the intended predictive or prognostic claim in the specific tumor type.

- The result would directly inform a specific, evidence‑based management decision (e.g., therapy selection or trial eligibility).

- Tissue‑based testing for the same biomarker is infeasible or would pose undue risk to the patient.

- The laboratory provides technical validation for CTC isolation and phenotypic detection methods and reports limitations (sensitivity, specificity, and failure rates).

Predictive classifiers and other named tests

Predictive classifiers and other named assays (examples). These assays may have context‑specific criteria; listed examples are not exhaustive. Coverage depends on meeting the distinct criteria for each named assay, and where present, refer to the related criteria groups above for overlapping indications.

Any of the following named tests may be reasonable and necessary when their individual, assay‑specific criteria are met:

- MyPRS Genetic Expression Profile Testing for multiple myeloma: reasonable only after initial diagnosis to stratify therapy, not for diagnosis or routine monitoring.

- Rosetta Cancer Origin Test™ (PROG): reasonable for cancer of unknown primary when conventional pathology and imaging cannot identify the primary.

- RosettaGX Reveal (thyroid microRNA test): applicable to indeterminate thyroid nodules per the thyroid criteria below.

- Tests with specific indications (e.g., Uveal Melanoma GNA11, gene‑specific assays) are covered only when the test’s analytic and clinical validity and intended‑use match the clinical scenario; consult individual test criteria or other sections in this policy for details.

Solid organ allograft rejection testing

Molecular testing for solid organ allograft rejection to detect rejection‑associated signatures. Tests are reasonable and necessary only when all criteria below are satisfied.

All of the following:

- Test is intended to detect acute or chronic rejection in a patient with a solid organ allograft where results would change immunosuppression management.

- Clinical context: symptoms, laboratory findings, or imaging raise concern for rejection and noninvasive testing would supplement, not replace, clinical judgment.

- The laboratory demonstrates analytic and clinical validation for the specific organ and intended use (acute cellular rejection, antibody‑mediated rejection, or chronic rejection signatures).

- Testing is performed in a CLIA‑certified laboratory and the report includes recommended clinical interpretation and suggested follow‑up.

Molecular testing for risk stratification of thyroid nodules

Molecular testing for risk stratification of thyroid nodules (consolidated). Tests for indeterminate cytology are reasonable and necessary when the following combined criteria are met; duplicate policy text has been consolidated into a single group.

All of the following:

- Index nodule criteria: Test is applied to a thyroid nodule with indeterminate cytology (Bethesda III–IV). For higher‑risk cytology (Bethesda V) the test may be considered in select cases when results would alter surgical extent or management.

- Test is intended to inform decision between surveillance, diagnostic lobectomy, or total thyroidectomy and when results will change management.

- Reflex/Concurrent testing: laboratories may perform reflex or concurrent molecular testing when previously established by institutional protocols and when such testing is documented to be medically necessary for the individual patient.

- Laboratory requirements: the performing laboratory must indicate the population and intended clinical indication for which the test has been validated and provide analytic and clinical validation data for the test in that population.

- Tests not meeting these criteria or lacking validation evidence for the indicated population are considered investigational/not covered.

Gene expression profile tests for decision-making in castration resistant and metastatic prostate cancers

Gene expression profile tests for castration‑resistant or metastatic prostate cancer used to inform treatment decisions. These assays are reasonable and necessary only when complex, context‑specific criteria below are satisfied.

All of the following (general requirements):

- Patient is being evaluated for management choices in castration‑resistant or metastatic prostate cancer where the test result would alter systemic therapy or other definitive management.

- The assay is analytically and clinically validated for the specific use and population.

- The test is intended for patients who are candidates for multiple therapeutic options and where genomic information directly informs selection.

Nested/branching criteria for candidate‑selection and exceptions (n_of logic):

At least 1 of the following

Assay will be used only when the patient is a candidate for multiple evidence‑based treatment options where assay results will guide selection;
Assay will not be used solely to prognosticate without linked treatment implications;
Assay use follows AV/CV/CU documentation standards and clinical guideline support for the specific indication.

- Exceptions: routine use for patients receiving palliative care where results would not change therapy, or use lacking analytic/clinical validation, is not covered.

General statements / cross-references

Cross‑references and general statements. Operational notes and links to related criteria are provided to aid navigation and consistent policy application.

Related criteria cross‑references:

- Solid organ allograft rejection testing: see Solid organ allograft rejection testing group for organ‑specific validation requirements.

- Melanoma risk stratification: see Melanoma risk stratification molecular testing for SLNB decision thresholds.

- Thyroid nodule testing: see Molecular testing for risk stratification of thyroid nodules for Bethesda criteria and laboratory validation requirements.

Contextual/guideline‑based coverage (tests/biomarkers supported or recommended by clinical guidelines):

- Tests and biomarkers supported by guideline bodies (e.g., NCCN, ASCO, CAP/AMP) and FDA‑approved companion diagnostics are generally considered reasonable and necessary when used for the guideline‑recommended indications and when performed in appropriately certified laboratories.

- Examples include tumor EGFR, ALK, ROS1, BRAF testing in NSCLC per guideline algorithms, BRCA1/2 germline testing for PARP inhibitor eligibility, and MSI‑H/dMMR testing for pembrolizumab eligibility in advanced solid tumors.

Evidence limitations and research needs:

- Many novel assays and broad genomic classifiers lack sufficient high‑quality clinical outcome evidence linking test results to improved patient outcomes; such assays remain investigational until adequate analytic and clinical validation and clinical utility evidence are established.

- Research needs include prospective trials demonstrating that assay‑guided management improves outcomes, standardized reporting of analytic validity metrics, and head‑to‑head performance comparisons for competing assays.

Coverage rationale and indications (summary of changes):

- This section consolidates policy positions to clarify appropriate use of unlisted codes and specific named assays, adds explicit NGS and NCD 90.2 applicability language, and defines operational documentation requirements for 81479 reporting.

- Clarified liquid biopsy (Guardant360®, InVisionFirst™) indications to require tissue infeasibility and intent to pursue further therapy tied to FDA/NCCN‑based biomarker indications.

- Added explicit thresholds (e.g., NGS MSI concordance >=95%, SLNB risk >5%) and consolidated duplicate thyroid nodule language into a single cohesive group.

Provider action / billing rules:

- Prior authorization: tests using unlisted codes or high‑cost comprehensive genomic profiling assays may require prior authorization per payer rules.

- Documentation: when reporting 81479 or other unlisted codes, include the test name, method, gene list, specimen type, analytic performance characteristics, and clinical interpretation in the submitted documentation to allow medical necessity review.

Tests with insufficient evidence (Not medically necessary / Not supported)

Covered only when evidence supports clinical utility; the following tests lack sufficient evidence and are not supported:

BluePrint® test (used with MammaPrint) — clinical utility insufficient at this time for Medicare).
40-GEP for cSCC: 40-GEP for cutaneous squamous cell carcinoma — no demonstrated additional prognostic benefit over guideline-based staging for NCCN very high-risk group.
HAX1 gene sequencing and panels including HAX1 — inadequate evidence of impact on management in Medicare population.
HTTLPR testing: Serotonin transporter genotyping (HTTLPR) — evidence conflicting and insufficient for coverage.
KIF6 genotype test — insufficient evidence to guide statin therapy across populations.
LPA-Intron 25 genotype test — insufficient evidence to support CAD risk assessment use.
PancraGEN® (Powered by PathfinderTG) — insufficient published evidence for analytical validity, clinical validity, or clinical utility; added to Non-Covered Indications for CPT 81479; no Medicare NCD; compliance with applicable LCDs required where applicable.
Prometheus IBD sgi Diagnostic test — insufficient evidence of clinical validity/utility to support use for differentiating IBD vs non-IBD and CD vs UC.
SULT4A1 testing: SULT4A1 genotyping — insufficient evidence to guide antipsychotic therapy.
VEGFR2 testing — insufficient evidence to establish association with treatment response for routine use.

Evidence limitations noted across reviewed studies include frequent small sample sizes, retrospective designs, selection bias, limited follow-up, lack of independent replication, and inconsistencies in analytic approaches. For many single-study or small retrospective reports the clinical evidence is insufficient to conclude impact on treatment decisions or outcomes for the Medicare population. The policy highlights the need for larger, well‑powered prospective studies, randomized trials, and independent validation cohorts (including prospective technical assessments) to establish clinical utility and to resolve uncertainties identified in existing data.

Denial Risk

Duplicate or redundant testing denial risk

Duplicate or redundant testing performed on the same biomarker, same specimen (surgical sample or aliquot), or for the same clinical indication will be denied as not medically necessary unless clinical justification is documented (e.g., evolution of tumor with new actionable variants or insufficient prior analytic performance).

Denial applies to repeat testing of same biomarker/sample/indication without documented medical necessity.
Affected code: CPT 81479

Documentation Required

PGx test ordering documentation

Orderers of pharmacogenomic (PGx) testing must document the clinical indication, medication(s) considered, and the actionable gene–drug pair being evaluated. Evidence-based actionable pairs should be cited in the medical record to support medical necessity and guide clinical decision-making.

Document medication(s) and intended use when ordering PGx tests.
Report PGx tests with appropriate codes and documentation; use CPT 81479 when no specific CPT exists

Prior Authorization

Prior authorization implied for unsupported tests

If an unlisted test lacks support from existing prior authorization pathways or applicable policy, a prior authorization or clinical review may be implied; submit clinical evidence and technical validation to support coverage. Laboratories may be asked to provide additional validation or peer-reviewed literature.

Submit AV/CV/CU evidence during prior authorization or clinical review.
Be prepared for requests for further validation before a coverage decision is made

Documentation Required

Clinical validation and literature requirement

Clinical validation must be supported by peer-reviewed literature or accepted evidence summaries; use evidence-based documentation to demonstrate intended use, clinical utility, and how results will inform diagnosis or management. When considering molecular testing, reference current evidence and society guidelines.

Provide peer-reviewed clinical validation or evidence summaries supporting the test's intended use.
Demonstrate how test results will inform diagnosis and patient management

Documentation Required

Use genomic testing to inform diagnosis and management

Genomic testing should be used to inform diagnosis and patient management per guideline-based indications. When tissue is insufficient, consider plasma-/ctDNA-based testing (liquid biopsy) as an alternative; document why tissue-based CGP was infeasible or insufficient.

Consider ctDNA/plasma-based testing when tissue is insufficient and document tissue insufficiency (QNS) or contraindication to biopsy.
Use NGS and matched normal when possible to improve analytic accuracy and interpretation.

Documentation Required

Use of NGS and monitoring considerations

When using NGS assays, include matched normal testing when feasible to help distinguish somatic from germline findings and reduce false positives. For MRD/ctDNA monitoring, specify testing frequency and operational examples in the medical record to support clinical utility.

Recommend use of NGS with matched normal when possible.
Provide operational examples for MRD/ctDNA monitoring frequency (e.g., post-treatment surveillance every 3 months for first year when supported by guideline or study; frequency must be justified in the chart).