Cigna Pharmacogenetic Testing Coverage Update

Coverage and Medical Necessity Criteria

Medical necessity criteria

Covered when ALL of the following are met

Primary criteria: The individual is a candidate for a targeted drug therapy associated with a specific gene biomarker or gene pathogenic/likely pathogenic variant.

Impact on care: The results of the pharmacogenetic test will directly impact clinical decision-making.

Analytical validity: The testing method is considered to be scientifically valid to identify the specific gene biomarker or gene pathogenic/likely pathogenic variant.

Evidence of benefit: EITHER identification of the specific gene or biomarker for use with a specific drug target has been demonstrated to improve clinical outcomes for the individual's condition OR identification of the gene biomarker is noted to be clinically necessary prior to initiating therapy with the drug as specified in the FDA-approved prescribing label.

Pharmacogenetic screening in the general population is not medically necessary. Gene expression classifiers or whole-blood gene expression profiling for predicting pharmacologic response are not covered or reimbursable. These determinations reflect the lack of supporting evidence for routine population screening or for use of whole-blood expression classifiers to predict drug response. Providers should order pharmacogenetic testing only when the individual is a candidate for a targeted drug therapy tied to a specific gene biomarker and when test results will directly impact clinical decision-making, and when the testing method is scientifically valid.

The policy explicitly identifies a list of CPT and HCPCS codes for specific single-gene tests and multigene pharmacogenomic/genomic panels that are not covered or reimbursable. Examples include single-gene CYP and other pharmacogenetic analyses (e.g., 81225, 81230, 81231, 81283, 81328, 81355) and multiple multigene panel PLA/CPT codes (e.g., 81418, 0029U, 0030U, 0031U–0033U, 0173U, 0175U, 0345U, 0347U–0350U, 0380U, 0392U, 0411U, 0419U, 0423U, 0434U, 0437U, 0438U, 0456U, 0460U, 0461U, 0476U, 0477U, 0516U, G9143) as listed in the Not Covered or Reimbursable sections.

Pharmacogenetic screening of asymptomatic individuals in the general population is considered not medically necessary. The literature review notes that clinical trials and outcome data supporting broad screening programs are lacking, and routine population-wide pharmacogenetic testing is not currently recommended.

The policy's Not Covered listings enumerate numerous CPT/PLA and HCPCS codes for which claims may be denied or not reimbursed when billed. These include, but are not limited to, single-gene and small-panel codes (e.g., 0031U, 0032U, 0033U) and a wide range of multigene panel and proprietary PLA codes (e.g., 0173U, 0175U, 0345U, 0347U–0350U, 0380U, 0392U, 0411U, 0419U, 0423U, 0434U, 0437U, 0438U, 0456U, 0460U, 0461U, 0476U, 0477U, 0516U, G9143). Providers should reference the full code list when submitting claims to determine reimbursement risk.

Covered indication — testing to guide use of a targeted drug therapy

Covered when ALL of the following are met

Indication: Testing is ordered to guide use of a targeted drug therapy when a specific gene biomarker is linked to that therapy.

Test method must be scientifically valid and evidence should show clinical benefit or be required by FDA label.

Impact on decision-making: Test results will directly impact clinical decision-making for selection, avoidance, or dosing of the targeted drug therapy.

Test validity: The testing method is analytically valid for the biomarker(s) being assessed (e.g., validated genotyping or variant analysis methodologies).

Refer to FDA guidance and technical standards for drug-metabolizing enzyme genotyping systems and pharmacogenetic tests.

Clinical evidence or regulatory requirement:

Covered indications — pharmacogenomic testing to inform drug selection/dosing

Covered when ALL of the following are met

Clinical context: Pharmacogenomic testing is ordered to inform drug selection or dosing for medications where gene–drug interactions are documented (examples include warfarin, clopidogrel, tamoxifen, antidepressants, tacrolimus).

Supported by guideline and literature references.

Evidence base: There is peer‑reviewed evidence, clinical practice guideline support, or FDA biomarker labeling linking the gene biomarker to the drug response or dose adjustment in the relevant clinical setting.

References: multiple studies and FDA biomarker table cited in policy (see reference list).

Analytical validity and reporting: The laboratory method used provides validated detection of the relevant variant(s) and reports clinically actionable results (e.g., metabolizer phenotype where applicable).

Refer to technical standards for pharmacogenomic test reporting (ACMG, FDA guidance).

Codes and Billing Status

Considered medically necessary when criteria metCPTCovered

81247	G6PD (glucose-6-phosphate dehydrogenase) (eg, hemolytic anemia, jaundice), gene analysis; common variant(s) (eg, A, A-).
81400	Molecular pathology procedure, Level 1 (eg, identification of single germline variant [eg, SNP] by techniques such as restriction enzyme digestion or melt curve analysis).
81401	Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat).
81405	Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis).
81227	CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, 2, 3, 5, 6).

Not Covered or ReimbursablemixedNot Covered

81225	CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug metabolism), gene analysis, common variants (eg, 2, 3, 4, 8, *17).
81230	CYP3A4 (cytochrome P450 family 3 subfamily A member 4) (eg, drug metabolism), gene analysis, common variant(s) (eg, 2, 22).
81231	CYP3A5 (cytochrome P450 family 3 subfamily A member 5) (eg, drug metabolism), gene analysis, common variants (eg, 2, 3, 4, 5, 6, 7).
81283	IFNL3 (interferon, lambda 3) (eg, drug response), gene analysis, rs12979860 variant.
81328	SLCO1B1 (solute carrier organic anion transporter family, member 1B1) (eg, adverse drug reaction), gene analysis, common variant(s) (eg, *5).
81355	VKORC1 (vitamin K epoxide reductase complex, subunit 1) (eg, warfarin metabolism), gene analysis, common variant(s) (eg, -1639G>A, c.173+1000C>T).
81418	Drug metabolism (eg, pharmacogenomics) genomic sequence analysis panel, must include testing of at least 6 genes, including CYP2C19, CYP2D6, and CYP2D6 duplication/deletion analysis.
0029U	Drug metabolism (adverse drug reactions and drug response), targeted sequence analysis (ie, CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, CYP4F2, SLCO1B1, VKORC1 and rs12777823).
0030U	Drug metabolism (warfarin drug response), targeted sequence analysis.
0031U	CYP1A2 (cytochrome P450 family 1, subfamily A, member 2)(eg, drug metabolism) gene analysis, common variants (ie, 1F, 1K, 6, 7).

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Not Covered CPT Codes (single-gene / small panels)CPTNot Covered

0031U	CYP1A2 (cytochrome P450 family 1, subfamily A, member 2)(eg, drug metabolism) gene analysis, common variants (ie, 1F, 1K, 6, 7).
0032U	COMT (catechol-O-methyltransferase) (eg, drug metabolism) gene analysis, c.472G>A (rs4680) variant.
0033U	HTR2A (5-hydroxytryptamine receptor 2A), HTR2C (5-hydroxytryptamine receptor 2C) (eg, citalopram metabolism) gene analysis, common variants (ie, HTR2A rs7997012, HTR2C rs3813929, rs1414334).

Not Covered CPT Codes (multi-gene panels)CPTNot Covered

0173U	Psychiatry (ie, depression, anxiety), genomic analysis panel, includes variant analysis of 14 genes.
0175U	Psychiatry (eg, depression, anxiety), genomic analysis panel, variant analysis of 15 genes.
0345U	Psychiatry (eg, depression, anxiety, attention deficit hyperactivity disorder [ADHD]), genomic analysis panel, variant analysis of 15 genes, including deletion/duplication analysis of CYP2D6.
0347U	Drug metabolism or processing (multiple conditions), whole blood or buccal specimen, DNA analysis, 16 gene report, with variant analysis and reported phenotypes.
0348U	Drug metabolism or processing (multiple conditions), whole blood or buccal specimen, DNA analysis, 25 gene report, with variant analysis and reported phenotypes.
0349U	Drug metabolism or processing (multiple conditions), whole blood or buccal specimen, DNA analysis, 27 gene report, with variant analysis.
0350U	Drug metabolism or processing (multiple conditions), whole blood or buccal specimen, DNA analysis, 27 gene report, with variant analysis and reported phenotypes.
0380U	Drug metabolism (adverse drug reactions and drug response), targeted sequence analysis, 20 gene variants and CYP2D6 deletion or duplication analysis with reported genotype and phenotype.
0392U	Drug metabolism (depression, anxiety, attention deficit hyperactivity disorder [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 (eg, depression, anxiety, attention deficit hyperactivity disorder [ADHD]), genomic analysis panel, variant analysis of 15 genes, including deletion/duplication analysis of CYP2D6.

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Not Covered HCPCS/G CodesHCPCSNot Covered

G9143

Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s).

Panel minimum gene count — CPT 81418

Minimum panel requirementFor CPT 81418 the panel must include testing of at least 6 genes, including CYP2C19 and CYP2D6 and CYP2D6 duplication/deletion analysis.

Relevant CPT code81418 — Drug metabolism genomic sequence analysis panel (threshold tied to gene count).

PurposeSpecifies minimum gene count required to meet the code description and policy coding expectations.

Panel gene count examples (13–40 genes)

Example panel sizes (multi-gene CPT/PLA codes)Documented examples of multi-gene panels range from 13 to 40 genes (examples: 13, 14, 15, 16, 19, 24, 25, 26, 27, 33, 40).

Prior Authorization, Documentation, and Billing Guidance

Prior Authorization

Prior Authorization Expectation

Providers should follow plan-specific prior authorization processes when applicable. Refer to the member's benefit plan document and any client-specific utilization management requirements prior to ordering testing.

Follow applicable prior authorization processes for the member's plan.
Claims for services without required prior authorization may be denied.

Denial Risk

Denial Triggers

Claims billed with diagnosis codes or services not covered under this policy will be denied. When billing, providers must use the most appropriate codes as of the date of service.

Services not accompanied by covered diagnosis or procedure codes will be denied.
Ensure coding aligns with the Coverage Policy and the member's benefit plan document.

Who May Order and Ordering Documentation

Note

Demonstrate intended drug therapy and clinical impact when ordering

Orderers must demonstrate the intended drug therapy and how test results will directly impact clinical decision-making; follow the member's benefit plan and any prior authorization processes when requesting testing.

Coverage is contingent on meeting the policy's medical necessity criteria linking testing to a targeted therapy.

Note

Guideline/technical references cited; ordering authority not specified

The document references clinical guideline sources and technical standards (including FDA guidance) but does not specify who may order these tests in the provided sections.

Exclusions and Not Reimbursable Services

Specific proprietary panels and individual gene tests are designated as Not Covered. Examples called out in the policy include multigene drug metabolism and psychiatry panels (e.g., PLA/CPT codes such as 0173U, 0175U, 0345U, 0347U–0350U, 0380U, 0392U, 0411U, 0419U, 0423U, 0434U, 0438U, 0476U, 0477U, 0516U) as well as individual gene analyses (e.g., 81225, 81230, 81231, 81283, 81328, 81355) and HCPCS G9143 for warfarin responsiveness testing. These tests are listed in the Not Covered or Reimbursable sections and therefore may not be reimbursed under this policy.

Gene expression classifiers and whole-blood mRNA profiling intended to predict pharmacologic response are explicitly not covered. The policy notes a lack of evidence supporting the use of such expression-based assays (for example, PLA/CPT code 0437U describing mRNA gene expression profiling of 15 biomarkers) for predicting medication response when performed on whole blood.

A broad set of pharmacogenomic and genomic panels and single-gene tests identified by CPT/HCPCS/PLA codes are listed as Not Covered or Reimbursable. The document lists code examples spanning single-gene assays (e.g., 0031U–0033U, 81225, 81230), psychiatry and drug metabolism panels (e.g., 0173U, 0175U, 0345U, 0347U–0350U, 0380U, 0392U, 0411U), larger multi-gene panels (e.g., 0419U, 0423U, 0434U, 0438U, 0460U, 0461U, 0516U), and HCPCS G9143. Claims submitted with these codes may be denied per the policy.

Additional not-covered statements in the Not Covered sections reiterate that various single-gene tests and multigene pharmacogenomic panels detailed by CPT/PLA/HCPCS codes in the policy are excluded from coverage. Providers should consult the full Not Covered code list in the policy when considering testing and claims submission to avoid denial risk.

Background and Scope

Pharmacogenetics studies how inherited genetic variation influences an individual’s response to medications, affecting drug metabolism, efficacy, and risk of adverse effects. Pharmacogenetic testing (e.g., genotyping, variant analysis) can guide drug selection or dosing when a specific gene biomarker is directly linked to a targeted therapy and when evidence shows that identifying the biomarker improves clinical outcomes or is required by the FDA-approved drug label. Clinical utility depends on analytical validity, clinical validity, and evidence that test results will alter clinical management to improve outcomes.

Terms and Test Definitions

Pharmacogenetic test — definition

DefinitionPharmacogenetic test: a laboratory assay (e.g., genotyping, variant analysis) used to identify gene biomarkers or pathogenic/likely pathogenic variants that influence drug response.

Method examplesGenotyping and variant analysis methods (e.g., targeted sequence analysis) are used to detect relevant gene variants.

Clinical aimIntended to guide treatment strategies and predict response to medication in specific clinical contexts.

Gene expression classifiers — definition and policy note

DefinitionGene expression classifiers: assays measuring RNA expression profiles (mRNA) to evaluate gene expression patterns.

Policy stanceGene expression classifiers and whole-blood profiling for predicting pharmacologic response are not supported due to lack of evidence for this use.

Testing Frequency and Repeat Testing

Frequency limits — summary

Frequency rule summaryNo explicit frequency limits or repeat testing intervals are specified in the cited policy chunks.

DocumentationFrequency limits section contains no defined numeric limits in the provided excerpts.

ImplicationAdjudicators should refer to plan documents or full policy for any member‑specific frequency constraints not present here.

Frequency limits — none specified in excerpts

No frequency limits specifiedThe document excerpts state that no frequency limits are specified in these chunks.

Reference guidanceReferences cited (FDA guidance, technical standards) may inform test validation but do not impose frequency rules in the provided text.

Policy Review and Change Log

2025-02-15Annual ReviewLatest

Annual review documented with no clinical policy statement changes.

2024-11-01Focused Review

Focused review documented with no clinical policy statement changes.

2024-02-15Annual Review

Annual review included a revised policy statement for biomarker genotyping/mutation analysis.

OpenPayer

Pharmacogenetic Testing Coverage Policy

Coverage and Medical Necessity Criteria

Codes and Billing Status

Prior Authorization, Documentation, and Billing Guidance

Who May Order and Ordering Documentation

Exclusions and Not Reimbursable Services

Background and Scope

Terms and Test Definitions

Testing Frequency and Repeat Testing

Policy Review and Change Log