CurrentUnitedHealthcarePolicy LABORATORY 023.22

Pharmacogenetic Panel Testing

UnitedHealthcare policy on pharmacogenetic multi-gene panel testing (panels of five or more genes) addressing coverage rationale, definitions, applicable procedure codes, and clinical evidence across psychiatric, cardiovascular, and oncology-related contexts.

Policy Summary

PayerUnitedHealthcare

PolicyPharmacogenetic Panel Testing

Policy CodePolicy LABORATORY 023.22

Change TypeUpdated CPT list; addition of 0533U

Effective DateApril 1, 2025

Next Review Date

Key ActionReference the member-specific benefit plan document and applicable laws to determine coverage and use CLIA-certified laboratories; documentation must support medical necessity per plan.

POLICY UPDATE CHANGES

Updated list of applicable CPT codes to reflect quarterly edits and added 0533U.

Archived previous policy version LABORATORY 023.21.

1Primary coverage stance (multi-gene panels)

~25Applicable molecular pathology/CPT/PLA codes referenced

3Major clinical areas discussed

21.5% vs 28.6%PREPARE trial ADR reduction

PPV 87.7%

PrismRA performance (select study)

Coverage Summary

Key summary

Primary coverage stance (multi-gene panels)Unproven and not medically necessary for any indication due to insufficient evidence of efficacy

Applicable codes referenced~25 CPT/PLA/Proprietary molecular pathology codes listed (examples: 0029U, 0173U, 0348U, 0438U, 0516U, 0533U, 81418)

Major clinical areas discussedPsychiatric, cardiovascular, oncology/anthracycline

Policy effective dateApril 1, 2025

Medical Necessity and Coverage Rationale

Coverage Rationale

Covered when ALL of the following are met:

ALL of the following

The use of pharmacogenetic Multi-Gene Panels (five or more genes) for the evaluation of drug-metabolizer status is unproven and not medically necessary for any indication due to insufficient evidence of efficacy.
The use of the PrismRAF molecular signature test is unproven and not medically necessary for evaluating likelihood of inadequate response to anti-TNF therapies for rheumatoid arthritis due to insufficient evidence of efficacy.

Clinical Evidence and Guideline Findings

Summarized findings from studies and professional society guidelines regarding PGx testing utility and recommendations:

ALL of the following

CPIC/ISPG/NCCN/STRIPE:

Not Medically Necessary / Experimental

Overall conclusion: Insufficient evidence of efficacy for pharmacogenetic multi-gene panels (five or more genes); unproven and not medically necessary for any indication. The PrismRA/MSRC molecular signature test is explicitly considered unproven and not medically necessary for predicting inadequate response to anti‑TNF therapies in rheumatoid arthritis due to very low-quality and insufficient evidence.

Applicable Procedure Codes

Referenced PLA / Proprietary molecular pathology / Pharmacogenetic panel codesmixed

0029U	metabolism (adverse drug reactions and drug response), targeted sequence analysis (i.e. CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, CYP4F2, SLCO1B1, VKORC1 and rs12777823) Drug
0173U	Psychiatry (i.e. depression, anxiety), genomic analysis panel, includes variant analysis of 14 genes
0175U
0345U	analysis panel, variant analysis of 15 genes, including deletion/duplication analysis of CYP2D6
0347U	Drug metabolism or processing, whole blood or buccal specimen, DNA analysis, 16 gene report, with variant analysis and reported phenotypes
0348U	Drug metabolism or processing, whole blood or buccal specimen, DNA analysis, 25 gene report, with variant analysis and reported phenotypes
0349U	Drug metabolism or processing, whole blood or buccal specimen, DNA analysis, 27 gene report, with variant analysis, including reported phenotypes and impacted gene-drug interactions
0350U	Drug metabolism or processing, whole blood or buccal specimen, DNA analysis, 27 gene report, with variant analysis and reported phenotypes
0392U	Drug metabolism (depression, anxiety, ADHD), gene-drug interactions, variant analysis of 16 genes, including deletion/duplication analysis of CYP2D6, reported as impact of gene-drug interaction for each drug
0411U	Psychiatry (e.g., depression, anxiety, ADHD), genomic analysis panel, variant analysis of 15 genes, including deletion/duplication analysis of CYP2D6

1–10 of 22

1/3

Applicable CPT / Proprietary Codes updatedmixed

0533U

Newly added code (policy history notes addition)

Provider Actions and Billing Guidance

Documentation Required

Benefit determination

Listing of codes is for reference only; inclusion does not imply coverage or reimbursement. Benefit coverage determined by member-specific plan and applicable laws; documentation must support medical necessity per plan.

0029U
0173U
0345U
0347U
0348U
0349U
0350U
0392U
0411U
0419U
0423U
0434U
0438U
0460U
0461U
0476U

Background and Evidence Summary

Pharmacogenetic multi‑gene panels are laboratory tests that assess multiple genes simultaneously (typically five or more) to predict drug response or metabolizer status; they differ from single‑gene or small targeted tests (e.g., 2–3 gene warfarin testing). This policy addresses multi‑gene PGx panels applied to psychiatric, cardiovascular, and chemotherapy‑related cardiotoxicity contexts and summarizes evidence, definitions, and applicable procedure codes.

High-level evidence takeaways

Overall coverage conclusionInsufficient evidence of efficacy for multi-gene panels; unproven and not medically necessary for any indication

PREPARE trialOpen-label cluster RCT (12-gene panel): reduced clinically significant ADRs — 21.5% PGx vs 28.6% control; among those with actionable results 21% vs 27.7%

PrismRA evidence summaryLimited, low-quality but suggestive data: nonrandomized cohorts and analytic validation report PPV ~87.7%, sensitivity ~60.2%, specificity ~77.3%; decision-impact and prospective cohorts report influence on prescribing but overall evidence judged very low quality by Hayes

Psychiatric RCTs/meta-analysesMixed RCT/meta-analysis results: some trials show early improvements in response/remission for MDD but with methodological limitations, inconsistent longer-term benefits

Revision History

04/01/2025revisedLatest

Updated list of applicable CPT codes to reflect quarterly edits and added 0533U.; Policy history line dated 04/01/2025 lists 'Updated list of applicable CPT codes... added 0533U.'

04/01/2025archived

Archived previous policy version LABORATORY 023.21.; Policy history indicates previous version archived on 04/01/2025.

Policy Summary

PayerUnitedHealthcare

PolicyPharmacogenetic Panel Testing

Policy CodePolicy LABORATORY 023.22

Change TypeUpdated CPT list; addition of 0533U

Effective DateApril 1, 2025

Next Review Date

Key ActionReference the member-specific benefit plan document and applicable laws to determine coverage and use CLIA-certified laboratories; documentation must support medical necessity per plan.

On This Page

Some gene-drug pairs (e.g., CYP2D6, CYP2C19, TPMT, HLA-A/B5701, HLA-A/B for carbamazepine/oxcarbazepine) have evidence supporting clinical actionability per CPIC, ISPG, NCCN and STRIPE assessments.

CPIC guidelines: provide actionable, evidence-based genotype-drug prescribing guidance for multiple genes (examples: CYP2D6, CYP2C19, CYP2B6); no CPIC recommendation for certain genes (HTR2A, SLC6A4) for SSRIs due to insufficient evidence.

ISPG recommendations: ISPG recommends HLA-A and HLA-B testing prior to carbamazepine and oxcarbazepine; supports CYP2C19 and CYP2D6 testing to inform antidepressant/antipsychotic selection and dosing; recommends screening POLG/OTC/CSP1 when valproate exposure is considered and mitochondrial/urea cycle disorder suspected.

NCCN: PGx testing may be considered before initiation or during treatment of pain when concerns of toxicity or lack of analgesic response are present; panel testing not specifically addressed.

STRIPE findings: STRIPE SDTF identified 21 gene-drug pairs with CPIC-level clinical actionability across therapeutic areas but found limited and inconsistent coverage in U.S. clinical practice guidelines and no information specific to tests including five or more genes.

Implementation limitations: Multiple implementation studies (e.g., University of Chicago 1200 Patients Project, national programs) show variable clinician uptake of PGx alerts and modest rates of medication change following actionable alerts; some programs demonstrated clinical impact (dose adjustments, selection changes) and potential cost estimates.

Multi-gene panel limitations: Limitations exist for multi-gene panels: variation in genes included, potential to miss rare/novel variants, variable analytic platforms, and lack of guideline support for many panel-included genes.

Documentation Required

Reference member-specific benefit plan

When deciding coverage, reference the member-specific benefit plan document and applicable federal/state mandates; member plan governs in event of conflict.

Documentation Required

Laboratory regulation requirement

Genetic tests are performed by CLIA-regulated laboratories; providers should use CLIA-certified labs for PGx testing.

Billing Rule

CPT code list maintenance (quarterly edits)

Applicable CPT codes are updated quarterly; policy history indicates CPT code list edits and addition of 0533U on 2025-04-01.

Affected code: 0533U
CPT code list updated quarterly per policy history

Providers should reference the member‑specific benefit plan document and applicable federal/state mandates to determine benefit coverage. Documentation submitted must support medical necessity per the plan and relevant laws; listing of procedure codes in the policy is for reference only and does not guarantee coverage or reimbursement.

Anthracycline studiesVariants associated with chemotherapy-induced cardiotoxicity identified (Stafford 2024; Yang 2021; Sagi 2018) but evidence insufficient for routine panel testing; findings vary by age and require prospective long-term validation

Multi-Gene Panel: Genetic tests that use next-generation sequencing to test multiple genes simultaneously.

PGx: Pharmacogenomic testing — genetic testing to guide medication selection or dosing based on genotype.

PrismRA / MSRC: A proprietary molecular signature response classifier (PrismRA) developed to predict non-response to anti‑TNF therapies in rheumatoid arthritis.

CPIC: Clinical Pharmacogenetics Implementation Consortium — produces genotype‑drug prescribing guidelines.