CurrentCentenePolicy N/A

V2.2023 Concert Genetics Genetic Testing Pharmacogenetics

Defines Centene-affiliated health plans' medical necessity and investigational determinations for pharmacogenetic panel and single-gene variant analyses, lists CPT/PLA codes and example tests, and summarizes guideline/evidence context. This is part 1 of 2 and includes policy criteria through multiple specific gene tests.

Policy Summary

PayerCentene

PolicyV2.2023 Concert Genetics Genetic Testing Pharmacogenetics

Policy CodePolicy N/A

Change TypeAdministrative/metadata clarification

Effective Date

Next Review Date

Key ActionDocument the specific clinical indication that meets the gene-specific medically necessary criteria and obtain prior authorization where required.

SourceLink

POLICY UPDATE CHANGES

Policy Date of Last Revision: 3/1/2023; Policy developed/revision date and approval date listed as 03/23

Policy developed and approved on 03/23 (Revision Date = 03/23, Approval Date = 03/23).

11+Single-gene tests with specific criteria listed

11Panel CPT/PLA codes listed as investigational

multipleExample commercial panels/tests referenced

MultipleReferences Cited

CPIC/NCCN/ASCOGuideline Sources

Coverage Summary

Defines coverage determinations for pharmacogenetic testing for Centene-affiliated health plans. The policy states that pharmacogenetic multi-gene panels (examples and CPT/PLA codes listed) are considered investigational for all indications, with specific single-gene exceptions described separately. It lists CPT/PLA panel codes (e.g., 81418, 0029U, 0345U and others) and notes the document includes single-gene criteria for many genes.

The policy scope covers germline pharmacogenetic tests used to assess drug response or toxicity risk, with methodologies including genotyping and single nucleotide variant testing, and summarizes professional guideline positions (CPIC, FDA, NCCN, ACMG) relevant to individual gene–drug pairs. While panels are investigational, certain multi-gene analyses such as combined TPMT and NUDT15 and specific HLA-B/HLA-A testing have separate non-investigational criteria.

Policy dates & quick facts

last_review2023-03-01

statusCURRENT

policy_titleCONCERT GENETIC TESTING: PHARMACOGENETICS

policy_header_datesPolicy developed/approved: 03/23 (Revision Date = 03/23, Approval Date = 03/23)

Single-gene tests with specific criteria listed11+

Panel CPT/PLA codes listed as investigational11

Medical-Necessity Criteria

Pharmacogenetic Panel Tests

Covered when ALL of the following are met:

ALL of the following

The test is a multi-gene pharmacogenetic panel specifically intended to guide medication selection or dosing for the individual being tested (examples include but are not limited to: GeneSight Psychotropic, OneOme RightMed, Professional PGX, PGxOne, Focused Pharmacogenomics Panel).
Results will be reviewed and applied by a qualified provider to guide a current or imminent medication decision for the member (e.g., selection, dosing, or avoidance of a specific drug).
Documentation is provided in the medical record that links the testing results to the planned medication management for the member (clinical note documenting how results affect drug choice or dosing).
Testing is ordered for the member being treated (not for family members) and results will be used in clinical decision-making for that member.

Evidence Summary and Clinical Utility

The policy summarizes guideline concordance and evidence: it cites multiple professional sources (CPIC, FDA, NCCN, ASCO) as informing recommendations and notes areas of agreement and uncertainty. It states that CPIC/FDA guidance informs many single-gene recommendations (for example, CPIC guidance on HLA-B*15:02 and carbamazepine and FDA labeling requiring CYP2C9 genotype assessment for siponimod).

On OPRM1 and COMT, the policy summarizes CPIC/implementation guidance that OPRM1 rs1799971 may be associated with a small (~10%) increase in postoperative morphine dose in some studies but is considered too modest to be clinically actionable; COMT rs4680 shows no consistent evidence for association with opioid adverse events and mixed evidence for analgesia or dose requirements.

For DPYD, the policy references CPIC guidance that testing may involve resequencing of the complete coding region or targeted analysis of known risk variants to guide fluoropyrimidine dosing, and notes that testing of other genes such as TYMS or MTHFR has unproven clinical utility.

Definition: the policy defines a Panel as a genetic test analyzing more than one gene and specifies that when billed as listed pharmacogenetic panels they are considered investigational.

Evidence snapshots

CPIC/FDA guideline concordancePolicy cites CPIC, FDA, NCCN, ASCO guidance across multiple genes and summarizes recommendations (e.g., CPIC HLA-B*15:02 avoidance with carbamazepine; FDA requires CYP2C9 genotype assessment prior to siponimod)

Coding

Pharmacogenetic Panel Test CPT/PLA Codes (panels considered investigational)CPTNot Covered

81418	Pharmacogenomic multi-gene panel
0029U	PLA code referenced in document
0030U	PLA code referenced in document
0033U	PLA code referenced in document
0173U	PLA code referenced in document
0345U	PLA code referenced in document
0347U	PLA code referenced in document
0348U	PLA code referenced in document
0349U	PLA code referenced in document
0350U	PLA code referenced in document

1–10 of 11

1/2

Single-gene Variant Analysis Codes - Medically Necessary or Investigational per geneCPT

81227	CYP2C9 variant analysis
81226	CYP2D6 variant analysis
0070U	CYP2D6 related PLA
0071U	CYP2D6 related PLA
0072U	CYP2D6 related PLA
0073U	CYP2D6 related PLA
0074U	CYP2D6 related PLA
0075U	CYP2D6 related PLA
0076U	CYP2D6 related PLA
81225	CYP2C19 variant analysis

1–10 of 21

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Example PLA/CPT codes for specific commercial panels/tests (informational list)mixed

0345U	GeneSight Psychotropic (Myriad) - listed as common CPT for panels
81418	Professional PGX (Genomind) - listed as common CPT for panels
0347U	OneOme RightMed PLA
0348U	OneOme RightMed PLA
0349U	OneOme RightMed PLA
0350U	OneOme RightMed PLA
0029U	Mayo Clinic Focused Pharmacogenomics Panel PLA
0030U	Mayo Warfarin Response Genotype PLA
0175U	Genomind Professional PGX Express CORE PLA referenced
0070U	CYP2D6 Common Variants and Copy Number (Mayo) PLA

1–10 of 19

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Common ICD-10 codes referenced (informational)ICD-10

F01-F69	Mental/behavioral disorders range referenced in document
F80-F99	Neurodevelopmental/behavioral disorders range referenced
Z81.8	Family history of other mental and behavioral disorders
Z86.59	Personal history of other infectious and parasitic diseases (listed contextually)
I20.0	Unstable angina
I21.01-I22.9	Acute myocardial infarction range
I24.1	Other forms of acute ischemic heart disease
I25.110	Atherosclerotic heart disease of native coronary artery with unstable angina
I63.50-I63.549	Cerebral infarction ranges referenced
B20	HIV disease (referenced for HLA-B*57:01 context)

1–10 of 12

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Provider Actions

Documentation Required

Ensure indication matches medically necessary criteria

Document the specific clinical indication that meets the gene-specific medically necessary criteria. Examples include: planned or ongoing clopidogrel therapy with PCI and ACS with high-risk features for CYP2C19 testing; planned eliglustat or siponimod therapy for CYP2D6/CYP2C9-related testing; planned abacavir therapy for HLA-B*57:01; planned carbamazepine or phenytoin therapy for HLA-B*15:02 and HLA-A*31:01; and initiation of thiopurine therapy or abnormal blood counts not responsive to dose reduction for TPMT/NUDT15. Ensure the medical record documents the drug therapy context and that the indication meets the listed coverage criteria.

Prior Authorization

Prior authorization likely required for single-gene testing

Coverage determinations are conditional on meeting medical necessity criteria; prior authorization should be obtained where required. When requesting authorization, reference the specific gene being tested and the applicable CPT or PLA code (single-gene codes such as 81225, 81226, 81227, 81232, 81381, 81306/81335/0034U/0169U, 81350, etc.) to support the request.

Definitions

Panel: a genetic test analyzing more than one gene; the policy specifies that pharmacogenetic testing panels (listed CPT/PLA codes) are considered investigational when billed as panels.

The definition is used to distinguish large multi-gene pharmacogenetic panels (investigational) from certain multi-gene analyses that have specific coverage criteria (for example, TPMT and NUDT15 and certain HLA-B/HLA-A analyses).

Revision History

2023-03-01clarified

Policy Date of Last Revision: 3/1/2023 (document header shows last revision metadata)

2023-03-23clarifiedLatest

Policy developed and approved on 03/23 (Revision Date = 03/23, Approval Date = 03/23) (administrative note)

Policy Summary

PayerCentene

PolicyV2.2023 Concert Genetics Genetic Testing Pharmacogenetics

Policy CodePolicy N/A

Change TypeAdministrative/metadata clarification

Effective Date

Next Review Date

Key ActionDocument the specific clinical indication that meets the gene-specific medically necessary criteria and obtain prior authorization where required.

SourceLink

On This Page

If the panel includes genes for which clinical utility is not established, those individual gene results will be considered investigational; coverage applies only to the use of panel results that are supported by peer-reviewed evidence and guideline recommendations for the specified medication decision.

CYP2C9 Variant Analysis (81227)

Medically necessary when ALL of the following are met:

ALL of the following

Testing is for CYP2C9 variant analysis (CPT 81227).
Results are intended to inform dosing or use of warfarin or another specific medication where CYP2C9 genotype has demonstrated actionable impact on drug safety or efficacy in peer-reviewed guidelines or authoritative drug labeling (e.g., warfarin dosing guidance combined with VKORC1 and clinical factors).
Documentation shows that CYP2C9 genotype information will be used by the treating clinician to make a specific medication decision for the member.

Investigational for other indications

CYP2C9 testing when used for broad panel screening without a defined medication decision or when used for indications lacking evidence of clinical utility (considered investigational).

CYP2D6 Variant Analysis (81226, 0070U-0076U)

Medically necessary when ANY of the following are met:

ANY of the following

CYP2D6 variant analysis (CPT 81226, 0070U-0076U) is ordered to determine metabolizer status to guide eliglustat therapy (to identify poor, intermediate, extensive/normal, or ultrarapid metabolizers as required by the eliglustat product labeling).
CYP2D6 testing is ordered to determine metabolizer status to guide siponimod dosing where CYP2D6 genotype impacts recommended dosing per product labeling or evidence-based guidance.
CYP2D6 testing is ordered when results will directly inform selection or dosing of a medication for the member and there is guideline or product-label support for a genotype-directed decision.

Investigational for other indications

CYP2D6 testing for indications without demonstrated clinical utility, for broad population screening without a specified medication decision, or as part of panels including genes lacking evidence-based actionability (considered investigational).

CYP2C19 Variant Analysis (81225)

Medically necessary when ALL of the following are met:

ALL of the following

CYP2C19 variant analysis (CPT 81225) is ordered for a patient with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) AND clopidogrel is being considered for antiplatelet therapy.
The clinician documents that CYP2C19 genotype results will be used to select or adjust antiplatelet therapy (for example, choosing an alternative agent for intermediate or poor metabolizers) consistent with guideline recommendations for genotype-guided antiplatelet therapy after PCI in ACS patients at elevated ischemic risk.
There is documentation that the patient is at high risk for recurrent ischemic events or otherwise meets clinical criteria where genotype-guided antiplatelet therapy is indicated (per guideline criteria or treating cardiologist assessment).

Investigational for other indications

CYP2C19 testing for indications other than the ACS + PCI + clopidogrel context described above, or for broad screening without a specific medication decision, is considered investigational due to insufficient evidence of clinical utility.

CYP4F2 Variant Analysis (81479)

Investigational for all indications:

CYP4F2 variant analysis (CPT 81479) is considered investigational for all clinical indications due to insufficient evidence demonstrating clinical utility in guiding medication therapy or improving patient outcomes.

DPYD Variant Analysis (81232)

Medically necessary when ALL of the following are met:

ALL of the following

DPYD variant analysis (CPT 81232) is ordered for a patient for whom fluoropyrimidine chemotherapy (e.g., 5‑fluorouracil, capecitabine) is being considered or planned, or for a patient who has experienced an unexplained severe toxicity to a fluoropyrimidine where DPYD results would inform subsequent dosing or drug selection.
Results will be used by the treating clinician to alter dosing, select an alternative therapy, or implement toxicity mitigation strategies based on established genotype–phenotype relationships and guideline recommendations.

Investigational for other indications

DPYD testing when ordered for indications not related to fluoropyrimidine therapy, or for broad screening without a specific chemotherapy decision, is considered investigational.

HLA-B*15:02 Variant Analysis (81381)

Medically necessary when ANY of the following are met:

ANY of the following

HLA-B*15:02 variant analysis (CPT 81381) is ordered prior to initiating carbamazepine in individuals of ancestries at increased risk for HLA-B*15:02–associated severe cutaneous adverse reactions (e.g., persons with relevant Asian ancestry) or when carbamazepine is being considered and results will guide avoidance of carbamazepine if allele present.
HLA-B*15:02 testing is ordered prior to initiating phenytoin in individuals at increased risk for HLA-B*15:02–associated severe cutaneous adverse reactions where results will inform drug selection or avoidance.

Investigational for other indications

HLA-B*15:02 testing for indications not tied to carbamazepine or phenytoin decision-making, or as part of broad panel screening without a specific medication decision, is considered investigational.

HLA-B*15:02 and HLA-A*31:01 Variant Analysis (81381)

Medically necessary when ALL of the following are met:

ALL of the following

Combined HLA-B*15:02 and HLA-A*31:01 variant analysis (CPT 81374, 81381) is ordered when carbamazepine therapy is being considered and results will be used to determine risk of hypersensitivity to carbamazepine to guide drug selection or avoidance.
Testing is for the patient who has clinical indications for carbamazepine therapy or is being considered for carbamazepine and the results will directly influence treatment choice.

Investigational for other indications

Testing of these HLA alleles for indications unrelated to carbamazepine prescribing decisions or for broad screening without a defined medication management plan is considered investigational.

HLA-B*57:01 Variant Analysis (81381)

Medically necessary when ALL of the following are met:

ALL of the following

HLA-B*57:01 variant analysis (CPT 81381) is ordered prior to initiating abacavir therapy and results will be used to avoid abacavir in individuals who are HLA-B*57:01 positive, consistent with product labeling and guideline recommendations.

Investigational for other indications

HLA-B*57:01 testing for indications other than abacavir prescribing decisions or for panel screening without a specific medication decision is considered investigational.

HLA-B*58:01 Variant Analysis (81381)

Medically necessary when ALL of the following are met:

ALL of the following

HLA-B*58:01 variant analysis (CPT 81381) is ordered prior to initiating allopurinol in individuals for whom allopurinol is being considered and results will be used to avoid allopurinol in allele-positive patients at increased risk for severe cutaneous adverse reactions.

Investigational for other indications

HLA-B*58:01 testing for indications unrelated to allopurinol prescribing decisions or for broad screening without a specific medication decision is considered investigational.

TPMT and NUDT15 Variant Analysis (81306, 81335, 0034U, 0169U)

Medically necessary when ANY of the following are met:

ANY of the following

TPMT and/or NUDT15 variant analysis (CPT 81306, 81335, 0034U, 0169U) is ordered prior to initiation of thiopurine therapy (e.g., azathioprine, mercaptopurine) to inform dosing or to determine need for alternative therapy based on predicted risk for myelosuppression/toxicity.
TPMT and/or NUDT15 testing is ordered for a patient receiving thiopurine therapy who develops abnormal complete blood count (CBC) or other signs of toxicity where genotype information would inform dose modification or change in therapy.

Investigational for other indications

TPMT and NUDT15 testing for indications not related to thiopurine therapy decisions, or for broad panel screening without a specific drug-management plan, is considered investigational.

UGT1A1 Variant Analysis (81350)

Medically necessary when ANY of the following are met:

ANY of the following

UGT1A1 variant analysis (CPT 81350) is ordered for a patient who will receive irinotecan chemotherapy and has elevated baseline bilirubin or clinical suspicion of Gilbert syndrome where genotype would influence dosing or monitoring to reduce risk of toxicity.
UGT1A1 testing is ordered for patients receiving irinotecan for cancer when results will directly inform dose modification or risk mitigation per guideline or product-label recommendations.
UGT1A1 testing is ordered prior to initiating atazanavir when an alternative regimen will be selected or counseling provided based on UGT1A1 status per drug labeling or evidence-based guidance.

Investigational for other indications

UGT1A1 testing for indications not related to irinotecan or atazanavir treatment decisions, or for broad screening without a specific medication plan, is considered investigational.

VKORC1 Variant Analysis (81355)

Investigational for all indications:

VKORC1 variant analysis (CPT 81355) is considered investigational for warfarin dosing and for all other indications due to insufficient evidence that testing improves clinically meaningful outcomes when used alone or in routine practice for warfarin management beyond standard clinical dosing algorithms and monitoring.

Other Single Gene Variant Analyses

Investigational for listed examples:

Other single-gene pharmacogenetic tests (examples, non‑exhaustive: COMT, CYP1A2, KIF6, OPRM1, SLCO1B1, TYMS) are considered investigational for use in routine clinical care when ordered to guide medication selection or dosing due to insufficient evidence of clinical utility. Individual genes not listed should be evaluated against current evidence and guidelines.

DPYD testing summaryDPYD testing may include full coding region resequencing or targeted analysis of known risk variants; recommended dose adjustments for carriers

OPRM1 rs1799971 effectStudies show ~10% increase in postoperative morphine dose for rs1799971 G allele in some studies; considered too modest to be clinically actionable

COMT rs4680 summaryNo evidence supporting association with opioid adverse events; mixed evidence for analgesia or dose requirements

Billing Rule

Panels considered investigational

Pharmacogenetic multi-gene panel CPT/PLA codes listed in the policy are considered investigational and claims billed with these panel codes will be adjudicated as investigational unless a specific exception in the policy applies. Use single-gene CPT/PLA codes when the member meets gene-specific medically necessary criteria instead of panel codes.

81418
0029U
0030U
0033U
0173U
0345U
0347U
0348U
0349U
0350U
0380U

Documentation Required

Reference to guideline-based evidence

Rely on CPIC and other professional guideline recommendations cited in the policy when considering pharmacogenetic testing. Document in the medical record the guideline-based rationale for testing (for example CPIC/FDA guidance on HLA-B alleles for carbamazepine, CPIC recommendations for TPMT/NUDT15 with thiopurines, FDA labeling for siponimod/CYP2C9) and how the test result will influence management.

Prior Authorization

Policy applicability and effective date adherence

Follow the Health Plan's effective date for this clinical policy and any state Medicaid or Medicare-specific requirements when requesting coverage or prior authorization. For Medicare members, review applicable NCDs/LCDs and Medicare coverage articles to ensure consistency with Medicare requirements.