CurrentUnitedHealthcarePolicy MMP210.32

Molecular Pathology/Molecular Diagnostics/ Genetic Testing

UnitedHealthcare medical policy defining reasonable and necessary indications, non-covered indications, and applicable CPT/HCPCS codes for a wide range of molecular diagnostic and genetic tests (including specific named commercial assays) applicable to Medicare Advantage and commercial members; includes references to applicable CMS NCDs/LCDs and related policies.

Policy Summary

PayerUnitedHealthcare

PolicyMolecular Pathology/Molecular Diagnostics/ Genetic Testing

Policy CodePolicy MMP210.32

Change TypeApplicable diagnosis code added; informational updates

Effective DateSep 1, 2025

Next Review Date

Key ActionDocument and order molecular tests only when clinical criteria in the policy are met and follow applicable LCD/LCA guidance.

POLICY UPDATE CHANGES

Diagnosis code D46.9 was added for CPT codes 81279, 81338, 81339, and 0027U.

Definitions section was added.

Clinical Evidence, FDA, and References sections were updated to reflect current information.

Previous policy version MMP210.31 was archived.

CMS Related Documents list updated to reflect the most current information in the Medicare Coverage Database.

8-30 mmBDX-XL2 nodule diameter range

>=40Minimum age for BDX-XL2 eligibility

<=50%Pre-test Cancer Risk (Mayo) for Coverage

97%BDX-XL2 sensitivity (validation subset)

Medicare exclusionPrenatal/Carrier Tests Not Covered

Coverage Summary & Scope

Scope: UnitedHealthcare's policy MMP210.32 defines reasonable/necessary and non-covered indications and applicable CPT/HCPCS codes for molecular diagnostic and genetic tests for Medicare Advantage and commercial members (effective 09/01/2025, last reviewed 08/13/2025). Coverage stance is summarized as mixed (covered when criteria met; many tests non-covered). Intended populations highlighted include Medicare Advantage members (references to NCD 90.2 and numerous MAC/LCD cross-references) and commercial members where LCDs/LCAs are not applicable.

Key BDX-XL2 intended-use thresholds summarized from the policy: patient age >= 40 years, lung nodule diameter 8–30 mm, and pre-test cancer risk by Mayo Clinic Model <= 50%; the test reports Likely Benign when post-test benign probability is >= 90% and PANOPTIC validation NPV ~ 98% (validation cohort n=178).

Medical‑Necessity Criteria (Selected Indications)

Covered / Reasonable and Necessary Indications (selected examples present in this part)

ANY of the following

ABL1 gene analysis, variants in the kinase domain is reasonable and necessary in patients with acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) to guide therapeutic decision making.
ASXL1 gene analysis is considered reasonable and necessary for prognosing patients with acute myeloid leukemia, myeloproliferative disease (essential thrombocytosis, myelofibrosis & polycythemia vera), and myelodysplastic syndrome.
KIT gene analysis is considered reasonable and necessary in patients who have gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), melanoma, and myeloproliferative disease to guide therapeutic decision making.
PDGFRA gene analysis is considered reasonable and necessary in patients with PDGFRA-associated chronic eosinophilic leukemia or GIST caused by mutations in the PDGFRA gene to guide therapeutic decision making.
Oncotype DX Breast Cancer Assay (21-gene RT-PCR, FFPE) is reasonable and necessary to guide therapeutic decision-making in: estrogen-receptor positive, node-negative carcinoma of the breast; estrogen-receptor positive micrometastases; and estrogen-receptor positive breast carcinoma with 1-3 positive nodes.
Oncotype DX DCIS assay is reasonable and necessary for women diagnosed with ductal carcinoma in situ (DCIS) who are planning on having breast-conserving surgery and considering adjuvant radiation therapy.
myPath Melanoma and other validated molecular DNA/RNA assays that aid in distinguishing melanoma from non-melanoma are reasonable and necessary when ordered by a board-certified/eligible dermatopathologist for an equivocal primary cutaneous melanocytic neoplasm after standard histopathology and ancillary testing have been performed, and when results may change management.
Pigmented Lesion Assay (PLA) is reasonable and necessary for use on melanocytic skin lesions with one or more clinical or historical characteristics suggestive of melanoma (including ABCDE criteria) when a clinician trained in skin cancer diagnosis is considering the need for biopsy to rule out melanoma; the PLA should not be used on clinically obvious melanoma and is one element of the overall clinical assessment.
PIK3CA testing is reasonable and necessary when used to identify PIK3CA-mutated HR-positive, HER2-negative advanced or metastatic breast cancer for which the FDA-approved companion therapeutic (alpelisib + fulvestrant) is being considered; testing should be performed using an FDA-approved test when indicated.
JAK2 exon 12 testing is reasonable and necessary to identify polycythemia vera (PV) when: genetic testing impacts medical management; the patient would meet WHO diagnostic criteria for PV if JAK2 exon 12 testing were positive; and prior JAK2 V617F mutation analysis was negative.
MPL gene testing is reasonable and necessary when genetic testing impacts medical management; prior JAK2 V617F mutation analysis was negative; and identification of a clonal marker would support a diagnosis of essential thrombocythemia (ET) or primary myelofibrosis (PMF) per WHO criteria.
Genetic testing of ASXL1, JAK2, MPL, CALR and other accepted myeloid mutation panels is reasonable and necessary to assist diagnosis, prognostication, and therapeutic decisions in myeloproliferative neoplasms including PV, ET, and PMF when results will impact management.
Use of molecular testing for indeterminate thyroid nodules (e.g., validated gene expression classifier or genomic sequencing classifier assays) is reasonable and necessary when cytology is indeterminate and testing results will influence the decision between surveillance and surgical management, and when the assay is validated for the intended clinical use.
Specific single-gene tests and focused disease panels (reasonable and necessary when impacting management): HBA1/HBA2 and HBB testing for hemoglobinopathies as clinically indicated; HTT (Huntingtin) testing for Huntington disease when there is compatible family history or clinical features and appropriate genetic counseling; targeted testing for common causes of congenital hearing loss; hereditary peripheral neuropathy panels for suspected Charcot-Marie-Tooth or related disorders when clinical features suggest a genetic etiology; hereditary retinal disorder panels for inherited retinal degenerations when ophthalmologic findings indicate a genetic diagnosis would alter management or counseling.

BDX-XL2 Coverage / Medical Necessity

ALL of the following

BDX-XL2 (Biodesix) is reasonable and necessary for management of a solitary pulmonary nodule between 8 and 30 mm in diameter in patients age ≥ 40 years with a pre-test probability of cancer (e.g., Mayo Clinic model) of ≤ 50%.
The intended use is to identify nodules with a high probability of being benign to support CT surveillance instead of invasive diagnostic procedures.
The test must be ordered by the treating physician managing the pulmonary nodule.
Operational note: The ordering physician's intent regarding surveillance versus invasive management should be documented in the medical record. Test performance is expected to result in surveillance rather than invasive evaluation in approximately 80% of cases where the test predicts low probability of malignancy; providers should document follow-up plan consistent with this intent.

Oncotype DX DCIS assay (and related specific genomic testing criteria)

Oncotype DX DCIS assay and Other Specific and Genomic Testing Criteria

ANY of the following

Oncotype DX DCIS assay (Genomic Health) is reasonable and necessary for women with ductal carcinoma in situ planning breast-conserving surgery who are considering adjuvant radiation therapy; requires formalin-fixed paraffin-embedded (FFPE) tissue specimen and use of the assay per intended clinical use.
Genome sequencing (WES/WGS)
- Whole exome sequencing (WES) or whole genome sequencing (WGS) is reasonable and necessary in individuals with unexplained constitutional or suspected heritable disorder/syndrome when: prior targeted testing (single gene, CMA, or disease-focused panel) was non-diagnostic or when the phenotype is genetically heterogeneous such that WES/WGS is more likely to yield a diagnosis; results will impact medical management, surveillance, or family planning; and appropriate pre- and post-test genetic counseling is documented.
Mitochondrial and nuclear-encoded mitochondrial testing

Not Reasonable / Not Covered / Experimental

Not Reasonable and Necessary / Non-Covered Indications

The following tests and categories are considered not reasonable and necessary for Medicare members (examples listed):

General non-covered categories: Molecular pathology tests for diseases/conditions that manifest severe signs in newborns/early childhood or result in early death; tests considered screening in absence of clinical signs/symptoms; carrier screening tests; prenatal diagnostic testing; tests on asymptomatic patients to determine risk for developing disease; tests without diagnosis-specific indications; pre-symptomatic genetic tests and services used to detect undiagnosed disease or predisposition — these are not Medicare benefits and will be denied as statutorily excluded where applicable.

Ordering practitioner must have established relationship and intend to use results per 42 CFR §410.32

Specific non-covered tests list: Examples of specific non-covered tests include: AFF2, AR, ASPA, BCKDHB, Cytogenomic genome-wide analysis for constitutional chromosomal abnormalities, DMPK, F9, FANCC, FMR1, FXN, G6PD, HBA1/HBA2, HBB, Hearing Loss Panel, Hereditary Peripheral Neuropathies Panel, Hereditary Retinal Disorders Panel, HTT, IKBKAP, MCOLN1, MECP2, Nuclear Encoded Mitochondrial Genes Panel, PMP22, SMN1, SMPD1, SNRPN/UBE3A, Whole Mitochondrial Genome, X-linked Intellectual Disability (XLID) Panel, DecisionDx-SCC and other molecular biomarker tests that risk stratify cSCC, MTHFR testing, OVERA and ROMA multi-marker ovarian cancer serum tests, Resolution ctDX Lung — these are listed as examples of non-covered services in the policy.

Clinical Evidence Summaries & Guideline Context

Narrative evidence summary: Genome sequencing (WES/WGS) and large-panel genomic approaches show increased diagnostic yield versus standard testing in many cohorts but insufficient high-quality outcome data for broad clinical utility; randomized neonatal trials (Krantz et al.) show earlier WGS increases changes in management and diagnostic yield but not length of stay or survival. BDX-XL2 (Biodesix) proteomic classifier validated in PANOPTIC (intended-use n=178) demonstrates high sensitivity and NPV and potential to reduce invasive procedures on benign nodules (~36% estimated) though prospective outcome studies are ongoing.

Specific test summaries: Oncotype DX GPS (prostate) has consistent observational evidence linking GPS to adverse pathology, recurrence, metastasis, and prostate cancer-specific mortality and is supported by NCCN for very-low/low/favorable intermediate risk men as a tool to assist risk stratification, though additional prospective utility studies are recommended. PIK3CA testing is supported as reasonable and necessary to identify PIK3CA-mutated HR+, HER2- advanced/metastatic breast cancer eligible for alpelisib (SOLAR-1, BYLieve) with PFS benefit; therascreen is the FDA companion diagnostic for tissue or liquid biopsy. ThyroSeq, ThyGeNEXT/ThyraMIR, and Afirma second-generation assays (ThyroSeq v3, Afirma GSC) show high sensitivity/NPV for indeterminate thyroid nodules (Bethesda III/IV) but performance and interpretation depend on local prevalence and NIFTP reclassification. PLA (Pigmented Lesion Assay) and myPath Melanoma have validation and real-world studies showing high sensitivity/NPV and impact on biopsy decisions and management when used as intended, but larger outcome studies are still desirable. Overall conclusion: many nucleic-acid/proteomic tests have promising analytic/clinical validity but larger prospective outcome studies demonstrating improved patient-centered outcomes are needed to confirm clinical utility for several indications.

Guideline and regulatory context: CMS NCD 90.2 for NGS is referenced as applicable for diagnostic NGS tests; where NCD/LCD silence or local coverage variance exists, MAC LCDs/LCAs and local contractor policies govern coverage and UnitedHealthcare follows those policies. ATA and NCCN guidance endorse selective use of molecular testing for indeterminate thyroid nodules (Bethesda III/IV) to supplement risk assessment and guide management decisions; NCCN also provides guidance on use of GPS in specified prostate populations. FDA regulatory note: alpelisib (Piqray) is approved for HR+, HER2-, PIK3CA-mutated advanced/metastatic breast cancer when a mutation is identified by an FDA-approved test; the FDA-approved companion diagnostic therascreen PIK3CA RGQ PCR Kit can be used on tissue and/or liquid biopsy. FDA testing pathway: if liquid biopsy (therascreen) is positive, treat per indication; if liquid biopsy is negative, a tumor (tissue) biopsy is required for PIK3CA testing.

Coding: CPT/Proprietary/ICD and Referenced LCDs/LCAs

Provider Actions & Requirements

Prior Authorization

Prior authorization and Medicare LCD/LCA compliance

Providers must follow applicable Medicare NCD/LCD/LCA requirements and the local MAC jurisdiction policies when ordering molecular diagnostic tests. Prior authorization requirements and coverage decisions are governed by those LCDs/LCAs and MACs where applicable. When a delegate manages utilization management or prior authorization for a Medicare Advantage member, follow the delegate's prior authorization requirements. Ordering practitioners must have an established patient relationship and must intend to use test results to manage the patient's specific medical problem.

Comply with CMS NCD 90.2 and applicable LCDs/LCAs/MAC policies for NGS and other molecular tests.
Follow local contractor (MAC) jurisdiction guidance (e.g., Noridian, Palmetto, NGS, CGS, First Coast, Novitas, WPS) for billing and coverage specifics.
Obtain prior authorization where required and follow delegate UM/prior authorization when applicable.
Ensure ordering practitioner has an established relationship with the patient and will use test results in clinical management (42 CFR §410.32).

Definitions

Term	Definition
MDT	Any test that involves detection/identification of nucleic acids (DNA/RNA), proteins, chromosomes, enzymes, chemotherapy sensitivity and/or other metabolites; may include multiple components or algorithms.
LDT	Any test developed by a laboratory without FDA approval or clearance.
Analytical Validity	Assessment of a test's technical performance (sensitivity, specificity, accuracy, precision); ability of the test to accurately and reliably detect the mutation and/or variant.
Clinical Validity	Ability of a test to classify a patient's circumstance into diagnostic, prognostic, or predictive functional category; ability to detect the disease of interest in the defined population.
Clinical Utility	Ability of a test to provide information related to patient care/management and to inform treatment decisions; CMS focuses on whether test use guides management and leads to improved health outcomes.
PLA	Pigmented Lesion Assay — a noninvasive adhesive patch gene expression test detecting LINC00518 and/or PRAME to assist biopsy decisions for suspicious melanocytic lesions.
GPS	Genomic Prostate Score — a 17-gene biopsy-based genomic assay providing a score (0-100) to help predict prostate cancer aggressiveness and adverse pathology.
DCIS Score	RNA-based assay score (Oncotype DX DCIS) predicting 10-year ipsilateral breast event risk in ductal carcinoma in situ; reported from FFPE tissue.
FFPE	Formalin-fixed paraffin-embedded tissue specimen type validated for many assays (e.g., Oncotype DCIS, myPath, ThyroSeq use FFPE).
Medicare member relevance	Tests for conditions manifesting in newborns/early childhood, prenatal diagnostic testing, and carrier screening are generally not relevant or covered for Medicare beneficiaries.
Likely Benign (BDX-XL2)	BDX-XL2 report category when post-test probability that a lung nodule is benign is 90% or higher (post-test benign probability / NPV metric per PANOPTIC validation).
BDX-XL2 NPV	BDX-XL2 negative predictive value (post-test benign probability) validated in PANOPTIC; example NPV 98% for XL_2(k) 0–0.131 (sensitivity 97%, specificity 44%).
BCR (Benign Call Rate)	Proportion of nodules tested with a 'benign' or 'negative' molecular result; used as a performance metric for rule-out tests (defined in definitions list).
NPV	Negative predictive value — probability the condition is absent given a negative test; performance depends on prevalence.
Rule-out test	Molecular test designed to identify benign nodules and avoid surgery (high sensitivity/NPV); described for thyroid and lung nodule contexts.
Rule-in test	Molecular test designed to predict aggressiveness of malignancy to aid surgical decision making (PPV-focused).
General test	Molecular test that can act as both rule-in and rule-out depending on intended use and performance characteristics.
PLA sampling	Four adhesive patches placed on lesion; lab dissects outlined tissue and performs RNA extraction from lesional tissue; positive if LINC00518 and/or PRAME detected.
XL_2(k)	BDX-XL2 numerical score between 0 and 1 calculated from 2 protein analytes and 5 clinical risk factors used to index post-test benign probability (reported bins with corresponding NPV).
BDX-XL2 intended use	Intended for 8–30 mm lung nodules in patients ≥40 years with pre-test Mayo Clinic Model cancer risk ≤50%; 'Likely Benign' when post-test benign probability ≥90%.
BDX-XL2 performance (PANOPTIC)	Validation (n=178 intended-use): sensitivity 97% (82-100%), specificity 44% (36-52%), NPV 98% (92-100%), PPV 25% (17-34%) — post-test probabilities and bin performance detailed.
myPath Melanoma	23-gene expression profile performed on FFPE sections as adjunct for diagnostically equivocal primary cutaneous melanocytic neoplasms; clinical validation sensitivity/specificity ~90-94%/91-96%.
Oncotype DX DCIS	RNA-based 12-gene DCIS Score reported from FFPE, predicts 10-year ipsilateral breast event risk; coverage criteria require DCIS pathology, FFPE ≥0.5 mm DCIS length, use to decide radiation vs surgery.
ThyroSeq / ThyraMIR / Afirma	Examples of molecular classifiers for indeterminate thyroid FNAs: ThyroSeq v3 (NGS genomic classifier), ThyGeNEXT/ThyraMIR, Afirma GSC — classified as rule-out/rule-in/general tests depending on validation metrics.

Medicare Determinations & LCD/LCA References

Name	Number	Type
Next Generation Sequencing (NGS)	NCD 90.2	NCD
Thyroid Nodule Molecular Testing	L38968	LCD
Biomarkers for Oncology	L35396	LCD
Molecular Pathology Procedures	L35000	LCD
MolDX: Molecular Diagnostic Tests (MDT)	L36021	LCD
BDX-XL2 (lung nodule classifier)	L37054 (examples L37062, L37031, L37216 shown)	LCD
Pigmented Lesion Assay (PLA)	L38111 (examples L38151, L38153, etc.)	LCD
Genetic Testing in Oncology: Specific Tests	L39365	LCD
MolDX: Plasma-Based Genomic Profiling in Solid Tumors (Resolution ctDx Lung)	L38065 (and related L39230,L39232)	LCD
MolDX: Predictive Classifiers for Early Stage NSCLC (DetermaRx)	L38284	LCD
MolDX: Prostate Cancer Genomic Classifier (GPS)	L38303 (and related L38341, L38339 etc.)	LCD
MolDX: Molecular Testing for Risk Stratification of Thyroid Nodules (MolDX variants)	L39650 / L39682 / L39684 (examples)	LCD
MolDX: Molecular Assays for Diagnosis of Cutaneous Melanoma (myPath)	L39389 (and related L39373,L39375 etc.)	LCD
MolDX: Plasma-Based Genomic Profiling in Solid Tumors (multiple LCDs)	various (e.g., L38043, L38065, L39230)	LCD
Multiple LCDs referenced for specific tests	various (e.g., L35396, L36117, L36021, L35000)	LCD

UnitedHealthcare will follow applicable Medicare National Coverage Determinations (NCDs), Local Coverage Determinations (LCDs), Local Coverage Articles (LCAs), and MAC contractor policies where relevant. Providers should reference and comply with the applicable LCD/LCA and MAC jurisdiction rules when ordering or billing molecular tests; UnitedHealthcare applies these Medicare guidelines for Medicare Advantage members and uses internal criteria when Medicare guidance is absent or allows local flexibility.

Revision History

09/01/2025material_changeLatest

Summary of Changes dated 09/01/2025: Diagnosis code D46.9 was added for CPT codes 81279, 81338, 81339, and 0027U.

09/01/2025added_information

Supporting Information: Definitions section was added.

09/01/2025updated_information

Supporting Information: Clinical Evidence, FDA, and References sections were updated to reflect current information.

Policy Summary

PayerUnitedHealthcare

PolicyMolecular Pathology/Molecular Diagnostics/ Genetic Testing

Policy CodePolicy MMP210.32

Change TypeApplicable diagnosis code added; informational updates

Effective DateSep 1, 2025

Next Review Date

Key ActionDocument and order molecular tests only when clinical criteria in the policy are met and follow applicable LCD/LCA guidance.

On This Page

Mitochondrial genome sequencing and nuclear-encoded mitochondrial gene panels are reasonable and necessary when there is clinical suspicion for a primary mitochondrial disorder and testing (mtDNA sequencing and/or nuclear gene panel) is likely to inform diagnosis, management, or genetic counseling; specimen requirements and assay validation for heteroplasmy detection should be considered.

HTT (Huntingtin) testing - Huntington Disease

HTT CAG repeat testing is reasonable and necessary when clinical features and/or family history are compatible with Huntington disease, when testing is performed with informed consent and pre- and post-test genetic counseling, and when testing will affect clinical management or reproductive planning.

Early-onset neurodevelopmental genes

Testing of MECP2, MCOLN1, IKBKAP and other genes associated with early-onset syndromes is reasonable and necessary when clinical presentation suggests these diagnoses and when results would alter medical management or surveillance and are ordered with appropriate counseling.

XLID multigene panels

X-linked intellectual disability (XLID) multigene panels are reasonable and necessary for males with unexplained moderate to severe intellectual disability with features suggestive of X-linked inheritance when results would inform management, prognosis, or family testing.

Specific gene tests and panels

HBA1/HBA2 and HBB testing for suspected alpha and beta thalassemia/hemoglobinopathies is reasonable and necessary when hematologic indices, hemoglobin electrophoresis, and clinical context indicate genetic testing would inform diagnosis or management.
Hearing loss gene panels (targeted or comprehensive) are reasonable and necessary when congenital or early-onset sensorineural hearing loss is present and identifying a genetic etiology would affect management, prognosis, or family counseling.
Hereditary peripheral neuropathy panels (including genes causing Charcot-Marie-Tooth and related disorders) are reasonable and necessary when clinical features indicate a hereditary neuropathy and results will impact management or family counseling.
Hereditary retinal disorder gene panels are reasonable and necessary when clinical ophthalmologic findings suggest inherited retinal degeneration and genetic diagnosis would change management or counseling.

Myeloproliferative neoplasm molecular criteria

Polycythemia vera (PV): JAK2 V617F or JAK2 exon 12 mutation testing is reasonable and necessary when results would influence diagnosis and management and when testing is used to meet WHO diagnostic criteria in the appropriate clinical context.
Essential thrombocythemia (ET): Testing for JAK2 V617F, CALR, and MPL mutations is reasonable and necessary when results will inform diagnosis per WHO criteria and guide management.
Primary myelofibrosis (PMF): Mutation analysis for JAK2, CALR, MPL, and other recommended myeloid panel genes is reasonable and necessary when results inform diagnosis, prognosis, and therapeutic decision-making.

Polycythemia vera (PV) and related molecular testing operational notes

When JAK2 V617F is negative and clinical suspicion remains for PV, JAK2 exon 12 testing is indicated. When a clonal marker is required to fulfil WHO criteria for MPD, testing of MPL, CALR or other myeloid mutations should be performed as clinically indicated.

PLA clinical utility/validity summary

Pigmented Lesion Assay (PLA): Clinical validity and utility support use in lesions with suspicious but not clinically obvious features; the PLA result should be integrated with clinical and dermatoscopic assessment to decide biopsy vs surveillance, and is not a sole determinant of management.

Other gene tests and evidence summaries

Other single-gene tests and multi-gene panels are considered reasonable and necessary when supported by clinical evidence or guideline recommendations demonstrating that results change medical management, prognosis, or genetic counseling; assays used should be validated for the intended clinical application.

Medicare relevance and exclusions

Medicare NCDs and LCDs: For NGS and other molecular tests, Medicare national and local coverage determinations (e.g., NCD 90.2 and applicable LCDs/LCAs) take precedence. Where LCDs/LCAs exist, compliance with their coverage criteria is required. In jurisdictions with no LCD/LCA or when LCDs are silent, UnitedHealthcare coverage criteria in this policy are applied.

Tests not endorsed or limited

Tests not endorsed or considered not medically necessary include laboratory-developed tests or multi-gene assays lacking clinical validity/utility evidence for the intended use, experimental or investigational assays, and redundant repeat testing when prior validated testing was conclusive. Specific tests may be listed as not covered in the Applicable Codes or Exclusions sections of this policy.

Guideline-supported uses

Guideline-supported uses: Molecular and genetic testing endorsed by professional society guidelines (e.g., NCCN, ASCO, ACMG) for specific indications are considered reasonable and necessary when performed consistent with guideline criteria and when results will impact clinical management.

PIK3CA regulatory/companion diagnostic

PIK3CA testing: Because alpelisib (Piqray) is FDA-approved for PIK3CA-mutated HR+/HER2- advanced or metastatic breast cancer with an FDA-approved companion diagnostic, PIK3CA testing is reasonable and necessary in this setting; testing should use an FDA-approved companion diagnostic when available.

In symptomatic adults use of some of these tests is unlikely to impact management and may be denied; Medicare exclusions apply

Concluding Medicare note: Note: Tests listed as non-covered may be denied as Medicare excluded tests; symptomatic adult use of these tests is unlikely to impact management and thus not reasonable and necessary. In accordance with CFR Title 42 §410.32, the referring/ordering practitioner must have an established relationship with the patient and use results in management.

Documentation Required

Required documentation and specimen requirements

Document the ordering clinician–patient relationship and the intended clinical use of the test. For specific tests, document the clinical criteria required by the policy: for JAK2 exon 12 testing document prior negative JAK2 V617F and that testing will affect management; for BDX-XL2 document patient age (≥40), nodule diameter (8–30 mm), and calculated pre-test Mayo Clinic Model risk (≤50%); for BDX-XL2 also document that the treating physician intends to act on the result. For myPath® Melanoma require that a board-certified/eligible dermatopathologist ordered the test and that the FFPE specimen is primary and representative; myPath requires FFPE tissue sections (5–7 sections, 4–5 μm). For Oncotype DX DCIS require pathology showing DCIS without invasive disease, FFPE specimen with ≥0.5 mm DCIS length, and documentation that the patient is considering breast-conserving surgery with or without radiation and will use the DCIS Score to decide between surgery alone vs surgery plus radiation. For PLA (Pigmented Lesion Assay) document that the lesion has ≥1 clinical/historical characteristic suggestive of melanoma (eg ABCDE) and that four adhesive patches were placed and lesion margins outlined for lab processing. Retain supporting documentation and be prepared to produce records to support coverage determinations.

Ordering practitioner relationship and intended use must be documented.
JAK2 exon 12: prior JAK2 V617F negative and testing will impact management.
BDX-XL2: document age ≥40, nodule 8–30 mm, Mayo Clinic pre-test risk ≤50%, and intent to act on result.
myPath® Melanoma: dermatopathologist order, primary FFPE specimen representative of suspicious area; FFPE sections (5–7 at 4–5 µm) required.
Oncotype DX DCIS: pathology confirming DCIS without invasive disease, FFPE with ≥0.5 mm DCIS length, patient considering breast-conserving surgery ± radiation and using result to choose therapy; no mastectomy planned.
PLA: lesion meets clinical suspicion criteria (eg ABCDE), four adhesive patches placed and lesion margins outlined; test not for clinically obvious melanomas.
Maintain and provide documentation to support coverage decisions upon request.

Denial Risk

High‑risk conditions for denial

Claims or orders are at high risk for denial when they fall outside policy-defined exclusions or intended-use criteria. Examples of high‑risk denial conditions include: billing Medicare for prenatal diagnostic testing, carrier screening, or presymptomatic screening (these are not Medicare benefits); ordering BDX-XL2 when the patient does not meet age (≥40), nodule size (8–30 mm), or Mayo pre-test risk (≤50%) criteria; ordering XLID multigene panels after Fragile X (FMR1) has already been ruled out (coverage risk due to insufficient evidence); ordering multigene XLID panels or other newborn/early-childhood disease tests for Medicare members (not relevant to Medicare); and ordering BDX-XL2 or similar intended-use tests when the treating physician does not intend to act on the result (BDX-XL2 should not be ordered without intent to act).

Prenatal diagnostic testing, carrier screening, and presymptomatic screening billed to Medicare — will be denied.
BDX-XL2 claims when patient is <40 years, nodule outside 8–30 mm, or Mayo pre-test cancer risk >50% — may be denied.
XLID multigene panels after Fragile X (FMR1) ruled out — coverage not supported (risk of denial).
Ordering BDX-XL2 when there is no intent to act on the result — inconsistent with coverage conditions and may be denied.
Tests for diseases manifesting in newborns/early childhood billed for Medicare members — likely denied as not relevant.

Billing Rule

Coding and claim submission guidance

Submit accurate CPT/HCPCS codes and follow MAC/LCD coding and billing guidance. CPT code listings and referenced LCDs/LCAs govern coverage where applicable; CPT descriptors are descriptive and do not guarantee payment. Use the relevant LCD/LCA and MAC jurisdiction guidance for coding; UnitedHealthcare follows Medicare contractor policies when applicable. For FDA companion diagnostic pathways (example: PIK3CA testing for alpelisib), follow the companion diagnostic algorithm — if an FDA‑approved liquid biopsy (therascreen PIK3CA RGQ PCR Kit) is positive use result to guide therapy; if liquid biopsy is negative, perform tumor tissue testing per FDA instructions.

Use accurate CPT/HCPCS and coding consistent with the LCD/LCA and MAC jurisdiction.
CPT code definitions do not guarantee payment — follow local Medicare contractor guidance.
Follow FDA companion diagnostic pathways (eg: positive liquid therascreen → treat; negative liquid therascreen → tumor tissue testing).
Refer to the policy's referenced LCDs/LCAs and MAC jurisdictions for billing/coding specifics.

09/01/2025administrative

Summary of Changes: Previous policy version MMP210.31 was archived.

09/01/2025administrative

Summary of Changes: CMS Related Documents list updated to reflect the most current information in the Medicare Coverage Database.