CurrentclearhealthalliancePolicy 1S-12

Next-generation sequencing (WES/WGS) and related molecular/genetic testing — Clinical coverage criteria

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Clinical coverage policy describing definitions, general description, and procedural context for next-generation sequencing (including whole exome and whole genome sequencing), plus related definitions and provisions; intended for Clear Health Alliance Medicaid beneficiaries and providers.

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CurrentclearhealthalliancePolicy 1S-12

Next-generation sequencing (WES/WGS) and related molecular/genetic testing — Clinical coverage criteria

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Policy Summary

Payerclearhealthalliance

PolicyNext-generation sequencing (WES/WGS) and related molecular/genetic testing — Clinical coverage criteria

Policy CodePolicy 1S-12

Change TypeNo material change

Effective Date

Last ReviewFeb 1, 2025

Next Review Date

Key ActionObtain and submit prior approval with supporting medical records when services exceed limits in Attachment A, Section C.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

10definition entries listed (1.1.1–1.1.10)

3major sequencing modalities described (NGS, WES, WGS)

CPT 81415–81427specific CPT codes referenced for WES/WGS and comparator/reanalysis

EPSDTEPSDT exception noted

CLIACLIA required

Coverage Criteria for NGS, WES, WGS and Molecular Profiling

WES Comparator / Reanalysis

Medicaid shall cover comparator exome analysis and reanalysis when specific conditions are met

Comparator exome analysis (CPT 81416): Comparator exome sequence analysis (CPT 81416) is covered when the WES criteria in Subsection 3.2.1(a) are met and WES is being performed simultaneously or has been previously performed.

Subsection 3.2.1(b).

Whole exome reanalysis (CPT 81417) of previously acquired uninformative WES is covered when either: 1) additional symptoms have emerged expanding the phenotype since the initial exome evaluation; or 2) a similarly affected first-degree relative is newly born or diagnosed and added to the clinical picture.

Subsection 3.2.1(c).

WGS Comparator / Reanalysis

Medicaid shall cover comparator genome analysis and reanalysis when specific conditions are met

Comparator genome analysis (CPT 81426): Comparator genome sequence analysis (CPT 81426) is covered when the WGS criteria in Subsection 3.2.1(d) are met and WGS is being performed simultaneously or has been previously performed.

Subsection 3.2.1(e).

Whole genome reanalysis (CPT 81427) of previously acquired uninformative WGS is covered when either: 1) additional symptoms have emerged expanding the phenotype since the initial genome evaluation; or 2) a similarly affected first-degree relative is newly born or diagnosed and added to the clinical picture.

Subsection 3.2.1(f).

Molecular Profiling / ctDNA

Medicaid shall cover molecular profiling for malignancies when ALL of the following are met

Molecular profiling for malignancy: 1) Beneficiary has a solid tumor that is inoperable or metastatic; 2) The purpose of testing is to evaluate tumor mutation burden (TMB); 3) The test is used to identify eligibility for checkpoint inhibition immunotherapy or targeted therapy; and 4) There are no viable alternative treatment options available.

Subsection 3.2.1(g).

ctDNA testing for precision therapy: Circulating tumor DNA (ctDNA) testing to direct precision cancer treatments is covered when the molecular profiling criteria in Subsection 3.2.1(g) are met and when formalin-fixed paraffin-embedded tumor tissue (FFPET) lacks sufficient quality or quantity or is unavailable for analysis.

Subsection 3.2.1(h).

Additional NGS Coverage Criteria

Medicaid shall cover NGS testing in addition when ALL of the following are met

Additional NGS requirements: a) A certified genetic counselor or the ordering provider evaluates and counsels the beneficiary pre- and post-test; b) Informed consent is obtained after genetic counseling and prior to testing; c) The test must guide treatment; d) The test must not be duplicative of another performed test; e) The test must be performed by a CLIA-certified laboratory; f) The test must be clinically valid based on published peer-reviewed literature and available for the suspected diagnosis; and g) The test must be scientifically valid for identification of a specific genetically linked disease or clinical condition.

Subsection 3.2.2.

Coverage with limitations

Coverage stance and when prior approval is required

General coverage: Medicaid shall not require prior approval for Genetic Testing - Next Generation Sequencing (NGS).

Subsection 5.1; see Attachment A, Section C for limits.

When prior approval is required: Prior approval is required when requested services exceed the testing limitations found in Attachment A, Section C.exceed Attachment A, Section C limits

Providers must follow prior approval submission requirements in Subsection 5.2.1.

Documentation to justify additional units: To request additional units for CPT codes listed in Attachment A, Section C, providers must submit: reason for the test(s); previous related laboratory results; explanation of how test results contribute to improved health outcomes; and explanation how results alter treatment and management.

Subsection 5.3.2; submit with prior approval per Subsection 5.2.1.

Medicaid does not cover whole exome sequencing (WES) or whole genome sequencing (WGS) when the specific coverage criteria in Subsection 3.2.1 are not met. In addition, WES/WGS is explicitly not covered for uncomplicated autism spectrum disorder, developmental delay, and mild to moderate global developmental delay. (See Subsection 4.2.1 for full list of not-covered scenarios.)

Providers should confirm that the beneficiary meets all conditions enumerated in Subsection 3.2.1 (for example, age limits and clinical features that justify WES/WGS) before submitting claims or prior approval requests; failure to meet those criteria may result in denial.

Molecular profiling for malignancies is not covered when the criteria in Subsection 3.2.1(g) are not satisfied. Coverage requires that the beneficiary has an inoperable or metastatic solid tumor, the test is intended to evaluate tumor mutation burden (TMB), the results are used to identify eligibility for checkpoint inhibition immunotherapy or targeted therapy, and no viable alternative treatments exist.

If these specific conditions are not documented, molecular profiling tests (including tissue- or ctDNA-based assays intended to direct precision cancer treatments) are not covered and may be denied.

The policy indicates under Section 4.2.2 that "Medicaid Additional Criteria Not Covered: None Apply." No separate state-specific Medicaid additional exclusions are listed in that subsection.

Providers should therefore rely on the specific not-covered items listed in Subsection 4.2.1 and the main coverage criteria when determining medical necessity for beneficiaries.

This policy does not reproduce CPT or HCPCS code descriptions. Providers must refer to the current CPT and HCPCS editions for authoritative code descriptions and instructions for use. When no specific code exists, providers must follow the CPT/HCPCS guidance for unlisted procedure or service and include a special report per the current coding manuals.

Claims must report diagnosis and procedure codes to the highest level of specificity that supports medical necessity, and providers should follow the Instructions for Use of the CPT Codebook and HCPCS National Level II when submitting unlisted codes or special reports.

The policy explicitly states that the use of WES or WGS for uncomplicated autism spectrum disorder, developmental delay, and mild to moderate global developmental delay is not covered. These indications are listed in Subsection 4.2.1 as scenarios in which WES/WGS shall not be covered.

Ordering providers should document alternative diagnostic rationale if they believe testing is medically necessary under different clinical circumstances that meet the covered criteria in Subsection 3.2.1.

Covered CPT codes for whole exome sequencing (WES) include 81415 (WES), with related comparator and reanalysis codes 81416 and 81417 listed as covered when their respective criteria are met in Subsection 3.2.1.

Providers should ensure the documentation demonstrates that all applicable coverage criteria for these codes are satisfied before billing.

Covered Indications and Special Populations

Unexplained congenital anomalies or neurodevelopmental disorders (≤21)

Unexplained congenital anomalies or neurodevelopmental disorders (≤21): Unexplained congenital anomalies or neurodevelopmental disorders in beneficiaries 21 years of age and younger when the beneficiary meets one of the high-probability genetic features (severe global developmental delay or intellectual disability; a family history strongly indicating a genetic etiology, including consanguinity; or developmental regression not related to autism or epilepsy) AND when criteria 2–5 of Subsection 3.2.1(a) are met (see WES initial coverage criteria).

Covered indication derived from Subsection 3.2.1(a).

Assessment of potential rare genetic conditions in NICU/PICU (≤21)

Critically ill neonates/children (≤21) in NICU/PICU: Assessment of potential rare genetic conditions using WGS is covered for beneficiaries 21 years of age and younger who are currently admitted to or recently discharged from a NICU or PICU, who demonstrate an abnormal response to standard therapy, whose phenotype lacks clear identification by established single-gene or multi-gene panels, and when criteria 4–5 of Subsection 3.2.1(d) are met (genetic diagnosis not ruled out regardless of prior testing or prior testing nondiagnostic with next steps invasive; symptoms not attributable to other causes).

Coding, CPT/PLA Codes, and Billing Rules

Covered CPT Codes - GenomeCPTCovered

81425	Whole genome sequencing (WGS)
81426	Comparator genome sequence analysis
81427	Whole genome reanalysis

Claims and CPT code limitations referenced (see Attachment A, Section C)mixed

No codes listed

Claim Typesmixed

CMS-1500	Professional claim type
837P	Professional electronic transaction
UB-04	Institutional claim type
837I	Institutional electronic transaction

Molecular Profilingmixed

81457	Molecular Profiling
81458	Molecular Profiling
81459	Molecular Profiling
81462	Molecular Profiling
81463	Molecular Profiling
81464	Molecular Profiling
0037U	Molecular Profiling
0048U	Molecular Profiling
0211U	Molecular Profiling
0239U	Molecular Profiling

1–10 of 13

1/2

NC Medicaid Genetic Testing - Next Generation Sequencing (NGS)mixed

0326U	NC Medicaid NGS
0329U	NC Medicaid NGS
0334U	NC Medicaid NGS
0364U	NC Medicaid NGS
0379U	NC Medicaid NGS
0388U	NC Medicaid NGS
0391U	NC Medicaid NGS
0395U	NC Medicaid NGS
0409U	NC Medicaid NGS
0414U	NC Medicaid NGS

Whole Exome Sequencing/Whole Genome Sequencingmixed

81415	Whole Exome/Whole Genome Sequencing
81416	Whole Exome/Whole Genome Sequencing
81417	Whole Exome/Whole Genome Sequencing
81425	Whole Exome/Whole Genome Sequencing
81426	Whole Exome/Whole Genome Sequencing
81427	Whole Exome/Whole Genome Sequencing
0094U	Whole Exome/Whole Genome Sequencing
0212U	Whole Exome/Whole Genome Sequencing
0213U	Whole Exome/Whole Genome Sequencing
0417U	Whole Exome/Whole Genome Sequencing

Genetic CounselingCPTCovered

96041

Genetic Counseling

Unlisted Procedure or Service guidanceneutral

No codes listed

Date of Service (DOS) rules

General DOS ruleThe Date of Service (DOS) for clinical diagnostic laboratory tests is the date the specimen is collected unless the physician orders the test at least 14 days after the beneficiary's discharge; when the 14-day rule applies, DOS is the date the test is performed.

ADLTs/molecular pathology exceptionFor Advanced Diagnostic Laboratory Tests (ADLTs) and molecular pathology tests performed after a hospital outpatient discharge, the DOS is the date the test is performed when conditions (a) through (e) in the CY2018 OPPS rule are met (test after outpatient discharge; specimen collected during outpatient encounter; medically appropriate collection at encounter; result does not guide treatment during encounter; test is reasonable and medically necessary).

Effect of exceptionWhen the ADLT/molecular pathology exception applies, the laboratory may bill under the Clinical Laboratory Fee Schedule and the test is unbundled from the hospital outpatient encounter (DOS = date performed).

Provider Actions, Prior Authorization, and Documentation

Prior Authorization

Prior approval required

Prior approval is required when requested services exceed the testing limitations found in Attachment A, Section C; otherwise Medicaid does not require prior approval for Genetic Testing - Next Generation Sequencing (NGS). Providers must follow the Prior Approval requirements in Subsection 5.2.1 when prior approval is required.

Medicaid shall not require prior approval for Genetic Testing - Next Generation Sequencing (NGS) except when exceeding Attachment A, Section C limits.
When exceeding Attachment A, Section C limits, submit prior approval per Subsection 5.2.1 to the DHHS Utilization Review Contractor.

Prior Authorization

EPSDT and prior approval do not waive prior authorization

EPSDT does not eliminate prior approval requirements: if the service requires prior approval, beneficiaries under age 21 still need prior approval. Refer to NCTracks and EPSDT guidance for additional provider instructions.

For beneficiaries <21, the EPSDT special provision does not waive prior approval when the service requires it.

Services Not Covered

The policy lists several categories of testing that are not covered, including prenatal fetal screening, preimplantation embryo testing, carrier screening, ancestry testing, and testing when the specific WES/WGS criteria in Subsection 3.2.1 are not met. It also specifies that WES/WGS is not covered for uncomplicated autism spectrum disorder, developmental delay, and mild to moderate global developmental delay.

Providers should verify that a requested test does not fall into these excluded categories before submitting a prior approval request or claim; documentation demonstrating how the clinical scenario differs from the excluded scenarios is required if coverage is being sought under an exception.

Definitions and Glossary

Checkpoint Inhibition Immunotherapy

DefinitionDrugs that target proteins (immune checkpoints) on immune cells and some cancer cells to block inhibitory signals, enabling T cells to more effectively kill cancer cells; used in cancer treatment.

Clinical useUsed to enhance anti-tumor immune responses and may be considered when tumor biomarkers (e.g., high TMB) indicate potential responsiveness to immunotherapy.

Mechanism summaryBlockade of checkpoint proteins removes restraints on immune activation, increasing T-cell-mediated tumor cell killing.

Close Relatives (First-, Second- and Third-Degree)

First-degree relativesParents, full siblings, and children.

Second-degree relativesGrandparents, grandchildren, aunts, uncles, nephews, nieces, and half-siblings.

Supplemental Provider Requirements

Note

Background and Context

Next-generation sequencing (NGS) technologies enable identification of genetic variants by determining nucleotide sequences. Whole exome sequencing (WES) targets the protein-coding regions of the genome (~1% of DNA), while whole genome sequencing (WGS) assesses nearly the entire genome (approximately 3 billion nucleotides), covering both coding and non-coding regions.

Molecular profiling or comprehensive genomic profiling is used to detect tumor biomarkers that may inform targeted therapies or eligibility for immunotherapies; the policy distinguishes these modalities and links appropriate coverage rules to clinical scenarios such as inoperable or metastatic solid tumors where no viable alternatives exist.

Policy Summary

Payerclearhealthalliance

PolicyNext-generation sequencing (WES/WGS) and related molecular/genetic testing — Clinical coverage criteria

Policy CodePolicy 1S-12

Change TypeNo material change

Effective Date

Last ReviewFeb 1, 2025

Next Review Date

Key ActionObtain and submit prior approval with supporting medical records when services exceed limits in Attachment A, Section C.

SourceLink

On This Page

Covered indication derived from Subsection 3.2.1(d).

Molecular profiling and ctDNA for solid tumors

Molecular profiling for inoperable/metastatic solid tumors: Molecular profiling to evaluate tumor mutation burden (TMB) and identify eligibility for checkpoint inhibitor immunotherapy or targeted therapy is covered for beneficiaries with inoperable or metastatic solid tumors when no viable alternative treatment options exist.

Subsection 3.2.1(g).

ctDNA when FFPET inadequate: Circulating tumor DNA (ctDNA) testing to direct precision cancer treatments is covered when the molecular profiling criteria are met and formalin-fixed paraffin-embedded tumor tissue (FFPET) lacks sufficient quality or quantity or is unavailable for analysis.

Subsection 3.2.1(h).

The policy defines close relatives for family history assessment as first-, second-, and third-degree relatives to support coverage decisions that rely on family history.

Use the specified degree definitions when documenting a family history that is asserted to strongly indicate a genetic etiology (for example, consanguinity or similarly affected relatives) in support of WES/WGS requests.

This section is reserved for additional eligibility top-level requirements or clarifications not already captured in the main coverage criteria. Any future additions will specify age, clinical setting, or documentation required to establish beneficiary eligibility.

This placeholder is reserved for other eligibility-related top-level nodes. If adopted, items here would describe beneficiary- or program-level eligibility constraints or exceptions relevant to genetic and molecular testing coverage.

Unit limitations

Molecular profiling codes - per primary cancerCPT/PLA codes 81457, 81458, 81459, 81462, 81463, 81464 and PLA codes 0037U, 0048U, 0211U, 0239U, 0242U, 0244U, 0250U are limited to once per primary cancer occurrence.

NC Medicaid NGS codes - per primary cancerPLA codes 0326U, 0329U, 0334U, 0364U, 0379U, 0388U, 0391U, 0395U, 0409U, 0414U are limited to once per primary cancer occurrence.

WES/WGS and comparator codes - lifetime limitsCPT/PLA codes 81415, 81416 (comparator once per comparator per lifetime), 81417, 81425, 81426 (comparator once per comparator per lifetime), 81427, 0094U, 0212U, 0213U, 0417U are limited to once in a lifetime (with comparator codes limited as specified).

See NCTracks Provider Claims and Billing Assistance Guide and the EPSDT provider page for details.

Prior Authorization

Prior authorization for NGS only when limits exceeded

Medicaid generally does not require prior authorization for NGS; prior approval is required only when a requested service would exceed the unit or frequency limits listed in Attachment A, Section C, and then must be submitted per Subsection 5.2.1.

NGS is not routinely subject to prior approval unless it exceeds Attachment A, Section C limitations.
Follow Subsection 5.2.1 for submission of prior approval requests and supporting records to the DHHS Utilization Review Contractor when required.

Billing Rule

Follow unit limitations on listed CPT/PLA codes

Adhere to the unit limitations listed in Attachment A for molecular profiling, NGS, WES/WGS, and genetic counseling codes when ordering and billing these tests; additional units require prior approval and supporting documentation.

Molecular profiling and many NGS PLA/CPT codes: once per primary cancer occurrence (see chunk 58 and 59).
WES/WGS and related codes (e.g., 81415, 81425, comparator/reanalysis codes): once in a lifetime or once per comparator per lifetime as listed (see chunk 60).
Genetic counseling (CPT 96041): limited to 3 units (90 minutes) (see chunk 61).

Step Therapy

Stepwise testing required before WES/WGS

Before pursuing WES or WGS, document that single-gene or targeted panel testing is not appropriate or does not match the clinical presentation; WES/WGS coverage requires that less comprehensive testing would be inappropriate or nondiagnostic.

Subsection 3.2.1 requires that the clinical presentation does not match a well-defined syndrome for which single-gene or targeted panel testing is available.
Coverage is supported when prior targeted testing was nondiagnostic or would be followed by invasive procedures as the next diagnostic step.

Documentation Required

Document genetic counseling content and informed consent

When genetic counseling is provided by a licensed provider (if a certified genetic counselor is not available), the provider must discuss and document the likelihood of disease, impact, possibility of modification, anticipated future developments, and that informed consent was obtained after the beneficiary verbalized understanding.

Document structured family/genetic history, multiple-generation pedigree, and genetic risk assessment per the genetic counseling definition.
Licensed providers must document: likelihood of developing disease; impact; possibility of modification; anticipated future developments; and informed consent after beneficiary verbalizes understanding.

Documentation Required

Document medical necessity and individualized testing rationale

Document that the requested test is individualized, consistent with the beneficiary's symptoms or confirmed diagnosis, and medically necessary; for beneficiaries under 21, include EPSDT-specific documentation when requesting exceptions to policy limits.

Subsection 3.2.2 requires certified genetic counselor or ordering provider evaluation and informed consent prior to testing.
EPSDT does not waive prior approval—include EPSDT documentation when applicable per Subsection 2.2.1.

Documentation Required

Supporting documentation required for additional units

When requesting additional units for CPT codes listed in Attachment A, Section C, include the reason for the test(s), previous related lab results, how results contribute to improved health outcomes, and how results will alter treatment and management.

Provide clinical justification and prior related results to support additional units.
Explain how test results will change beneficiary management and improve outcomes.

Prior Authorization

Include complete health records with prior approval request

Submit the prior approval request and all health records or other records that support the beneficiary meets the specific criteria in Subsection 3.2 to the DHHS Utilization Review Contractor when prior approval is required.

The prior approval packet must include the prior approval request plus all health records and documentation supporting criteria in Subsection 3.2.
Failure to submit required records may trigger denial when prior approval is required.

Billing Rule

Use most specific ICD-10-CM and CPT/HCPCS codes

Report diagnosis and procedure coding to the highest level of specificity that supports medical necessity and use current CPT/HCPCS/UB-04 editions; if no specific code exists, report using the appropriate unlisted code.

Providers shall report ICD-10-CM and PCS to the highest level of specificity that supports medical necessity (Attachment A Section B).
Use the most specific CPT/HCPCS/UB-04 codes available; if none exist, use the appropriate unlisted procedure or service code (Attachment A Section C).

Prior Authorization

Prior approval referenced in policy; follow Subsection 5.2.1

Prior approval processes are referenced in both the 'Requirements for and Limitations on Coverage' and 'Prior Approval Requirements' sections; failure to obtain prior approval when required may result in denial.

Policy explicitly references Prior Approval and Prior Approval Requirements under Requirements for and Limitations on Coverage.
If prior approval is required (per Attachment A limits), follow Subsection 5.2.1 to avoid denial.

Denial Risk

Triggers for denial based on eligibility, criteria, duplication, or investigational status

Tests or claims may be denied if the beneficiary does not meet eligibility in Section 2.0 or the specific criteria in Section 3.0, if the service duplicates another provider's service, or if the procedure is experimental, investigational, or part of a clinical trial.

Denial triggers include failure to meet Section 2.0 eligibility or Section 3.0 coverage criteria.
Duplicative services and investigational/clinical trial procedures are noncovered and may be denied.

Prior Authorization

Submit complete prior approval packet to DHHS Utilization Review Contractor

If prior approval is required, the provider must submit the prior approval request and all supporting health records/documentation to the DHHS Utilization Review Contractor per Subsection 5.2.1; failure to do so may result in denial.

Prior approval submissions must include the prior approval request and all supporting health records per Subsection 5.2.1.
When requesting additional units, include the specific supporting documentation listed in Subsection 5.3.2.

Denial Risk

Risk of denial for nonspecific or inaccurate coding

Claims that do not report the most specific CPT/HCPCS/UB-04 revenue code accurately describing the procedure, or that fail to use appropriate ICD-10-CM specificity, may be noncompliant and risk denial.

Provider(s) shall report the most specific billing code that accurately and completely describes the procedure (Attachment A, Section C).
Report ICD-10-CM and PCS to the highest level of specificity that supports medical necessity (Attachment A, Section B).

Documentation Required

Require pre/post-test counseling and document informed consent; CPT 96041 limited to 3 units

A certified genetic counselor or the ordering provider must perform pre- and post-test evaluation and counseling and obtain informed consent prior to testing; genetic counseling is billable under CPT 96041 with a unit limit of 3 units (90 minutes).

Subsection 3.2.2(a) requires evaluation and counseling by a certified genetic counselor or ordering provider pre- and post-test.
CPT 96041 is limited to 3 units (1 unit = 30 minutes), 90 minutes total (Attachment A).
Licensed providers providing counseling when no certified counselor is available must document the counseling elements and informed consent (Subsection 1.1.5).

Third-degree relativesFirst cousins, great-grandparents, and great-grandchildren on the same side of the family.

Consanguinity

DefinitionA close biological relationship between individuals who share a common ancestor; signifies a blood tie or kinship (e.g., parents, siblings, grandparents, cousins).

Context of useRelevant in assessing family history and genetic risk where consanguinity increases likelihood of recessive conditions.

ImplicationMay be considered a qualifying feature for WES coverage when family history strongly indicates genetic etiology.

Genetic Counselor

DefinitionHealth professionals with specialized education, training, and experience in medical genetics and counseling, certified by the American Board of Genetic Counseling or holding Active Candidate Status.

RoleHelp beneficiaries understand and adapt to genetic contributions to disease and assist with decision-making about testing and management.

Billing/supervision noteServices may be provided under supervision or contract arrangements as described in policy when certified counselors are unavailable.

Genetic Counseling

DefinitionA communication process enabling beneficiaries and families to make informed medical decisions, including structured family/genetic history, multi-generation pedigree, genetic risk assessment, and counseling on natural history, recurrence risk, and testing/screening/monitoring options.

Licensed provider provisionIf no certified genetic counselor is available, a licensed provider may provide counseling but must document likelihood of disease, impact, modification possibilities, anticipated future developments, and that informed consent was obtained.

Consent requirementInformed consent must be obtained after the beneficiary verbalizes understanding of the procedure, benefits, limitations, and possible consequences.

Molecular Profiling

DefinitionComprehensive genomic profiling (molecular profiling) is a technique used to detect biomarkers within a cancerous tumor to identify potential treatment options.

PurposeDetect actionable tumor biomarkers that may inform targeted therapies or immunotherapy eligibility.

ApplicationUsed for inoperable or metastatic solid tumors to evaluate TMB and identify therapy options when no viable alternatives exist.

Phenotype

DefinitionObservable characteristics of a beneficiary resulting from the interaction between genes and the environment.

Use in policyPhenotype description guides selection of genetic tests; expanded or changing phenotypes may justify reanalysis.

ExampleDevelopmental regression or atypical features that broaden phenotype may support coverage for WES/WGS reanalysis.

Tumor Mutation Burden (TMB)

DefinitionTumor Mutation Burden (TMB) is the overall count of somatic mutations detected in cancer cell DNA; higher TMB can indicate increased responsiveness to certain immunotherapies.

Clinical relevanceTMB assessment may be used to identify eligibility for checkpoint inhibitor immunotherapy.

Role in molecular profilingIncluded as an objective of molecular profiling for inoperable or metastatic solid tumors per coverage criteria.

Whole Exome Sequencing (WES)

DefinitionWhole Exome Sequencing (WES) is a laboratory technique that sequences the exonic (protein-coding) regions of the genome—approximately 1% of the DNA and associated sequences.

ScopeFocuses on coding regions and associated sequences rather than the entire genome.

Coverage implicationWES is covered for specified indications (e.g., unexplained congenital anomalies/neurodevelopmental disorders in beneficiaries ≤21) when policy criteria are met.

Whole Genome Sequencing (WGS)

DefinitionWhole Genome Sequencing (WGS) is a laboratory process to determine nearly all of a beneficiary's complete DNA sequence, covering roughly 3 billion nucleotides including coding and non-coding regions.

ScopeProvides comprehensive assessment of coding and non-coding genomic regions versus WES which targets exons.

Clinical useWGS is covered for critically ill neonates/children in or recently discharged from NICU/PICU with abnormal response to standard therapy when policy criteria are met.

Whole Exome Sequencing (alternate)

Definition (alternate)Whole exome sequencing focuses on sequencing exonic regions and associated sequences, representing about 1% of the genome.

Relation to WES codesAssociated CPT/PLA codes for WES are listed in policy Attachment A and subject to unit limitations.

Clinical implicationUsed when phenotype and prior testing support exome-level analysis per coverage criteria.

Whole Genome Sequencing (alternate)

Definition (alternate)Whole genome sequencing assesses nearly all of a beneficiary's DNA sequence, including coding and non-coding regions, totaling approximately 3 billion nucleotides.

Relation to WGS codesAssociated CPT/PLA codes for WGS are listed in policy Attachment A and subject to unit limitations.

Clinical implicationConsidered when broad genomic analysis is required and policy criteria for WGS are met.

Molecular profiling / NGS / WES/WGS codes

Code lists includedPolicy lists CPT and PLA codes for molecular profiling, NC Medicaid NGS, and WES/WGS with associated unit limitations in Attachment A (e.g., 81457–81464, 0037U, 0048U, 0211U, 0239U, 0242U, 0244U, 0250U; 0326U–0414U; 81415–81427, 0094U, 0212U, 0213U, 0417U).

Purpose of listsThese code lists define billing/claim restrictions and unit limitations (once per primary cancer occurrence or once in a lifetime) referenced elsewhere in the policy.

Where to find detailsSee Attachment A, Section C in the policy for the full code tables and limits referenced in the coverage rules.

Genetic counseling (CPT 96041) unit limitation

CPT 96041 unit limitCPT code 96041 (genetic counseling) is limited to 3 units (1 unit = 30 minutes), for a maximum of 90 minutes total.

Billing noteGenetic counseling is billable under CPT 96041 when requirements for pre- and post-test counseling and documentation are met.

Documentation requirementCounseling must include structured family history, pedigree, risk assessment, discussion of natural history/recurrence risk, testing options, and documented informed consent per policy guidance.