ModifiedUnitedHealthcarePolicy MMP381.22

Tier 2 Molecular Pathology Procedures

Defines coverage rationale, coding, and Medicare-related applicability for Tier 2 molecular pathology (genetic/molecular) procedure codes and the circumstances under which such tests are reasonable and necessary for UnitedHealthcare Medicare Advantage members.

Policy Summary

PayerUnitedHealthcare

PolicyTier 2 Molecular Pathology Procedures

Policy CodePolicy MMP381.22

Change TypeMaterial updates to Non‑Covered Diagnosis Codes and policy versioning

Effective DateMay 1, 2025

Next Review DateN/A

Key ActionUse the appropriate Tier 2 molecular pathology CPT code and provide documentation showing alternative tests are unavailable or equivocal and that results will directly impact management.

SourceLink

POLICY UPDATE CHANGES

Applicable diagnosis code Z83.72 was added to the Non-Covered Diagnosis Codes list.

Applicable diagnosis code Z59.1 was removed from the Non-Covered Diagnosis Codes list.

Previous policy version MMP381.21 was archived and replaced by this version.

9Tier 2 CPT Codes listed

Many testsMedicare utility: insufficient

2ClinGen strong actionability

1Diagnosis code added

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

1Diagnosis code removed

Coverage Criteria and Clinical Rationale

Medicare reasonable and necessary criteria

Tier 2 molecular pathology procedures are reasonable and necessary when ALL of the following are met

Medicare reasonable and necessary criteria: Alternative laboratory or clinical tests to definitively diagnose the disorder/identify the condition are unavailable or results are clearly equivocal

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Clinical validity: Availability of a clinically valid test, based on published peer reviewed medical literature

[[chunk 7]]

Analytic validity: Testing assay is Food and Drug Administration (FDA) approved/cleared, or is a laboratory-developed test (LDT), or an FDA-modified test that supports assay analytical validity and clinical utility

[[chunk 7]]

Impact on management: Results of the testing must directly impact treatment or management of the member

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Panel size restraint: For testing panels, and where a tiered approach/method is clinically available, testing is reasonable and necessary only for the number of genes or tests that are reasonable and necessary to establish a diagnosis

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Prior testing: Individual has not previously received genetic testing for the disease/condition; diagnostic genetic testing for an inherited disease should generally be performed once in a lifetime

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Not covered/limited uses

Nationally Non-Covered Indications

Screening/presymptomatic tests: Screening services, such as pre-symptomatic genetic tests and services used to detect an undiagnosed disease or disease predisposition, are not covered unless explicitly authorized by statute

[[chunk 16]]

Tests without demonstrated management impact: Tests that do not clearly and directly affect patient management or lack reasonable and necessary evidence are not covered

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Evidence insufficiency for many individual Tier 2 genetic tests

Summary conclusion for the Medicare population in this section

Insufficient evidence for Medicare clinical utility: Due to low quality or insufficient evidence, the clinical evidence reviewed for the individual Tier 2 genetic tests in this section is insufficient to conclude these tests impact therapeutic decision-making or directly impact treatment, outcome, and/or clinical management in the care of the Medicare member.

applies to the genes individually discussed in chunks 57-73

Usher syndrome testing

Evidence supports molecular screening for Usher syndrome when hearing impairment is present

Usher testing criteria: Covered when patients have hearing impairment and/or combined visual symptoms where identification of biallelic mutations informs diagnosis and future ophthalmologic risk

Authors recommend early molecular screening in deaf children; 7.5% of isolated sensorineural deafness had Usher gene mutations; USH2A accounts for ~50% of biallelic mutations

Charcot-Marie-Tooth (CMT) testing

CMT genetic testing sequence recommended by consensus

CMT testing sequence: Covered when following sequential approach: test for PMP22 duplication first in demyelinating/undetermined forms; if negative, perform NGS panel including GJB1, MPZ, PMP22, SH3TC2, MFN2, GDAP1, MME, HSPB1 and consider sequencing/CNV analysis of additional genes

Mascaró et al. 2024 consensus guideline recommends this order

NF2 testing

NF2-related testing context and relevance

NF2 testing indications: Covered when clinical and imaging findings consistent with vestibular schwannoma or NF2, as NF2 inactivation is a known driver and molecular alterations are prevalent in certain tumors

MRI with gadolinium is gold standard for VS diagnosis; NF2 alterations found in >=10% of mesothelioma cohort and are relevant to tumor biology

Gene-specific evidence summaries and coverage-relevant notes

Summaries of evidence and testing considerations by gene:

MPZ / CMT testing: For suspected Charcot-Marie-Tooth (CMT), clinical diagnosis followed by neurophysiological testing then genetic testing: first test for PMP22 duplication in demyelinating/undetermined forms; if negative consider NGS panel including GJB1, MPZ, PMP22, SH3TC2, MFN2, GDAP1, MME, HSPB1; consider full sequencing of GJB1, SORD, MT-ATP6 and CNV analysis in other genes.

Reflects consensus guideline recommendation for sequential testing.

NF2 inactivation contributes to vestibular schwannoma (VS) and both alleles are often inactivated; MRI with gadolinium is gold standard for VS diagnosis. NF2 alterations occur in ~10% of mesothelioma cases; genetic testing may identify molecular drivers relevant to targeted therapy research.

Evidence graded medium/low; potential relevance for personalized therapeutics.

Pediatric-onset metabolic and genetic disorders: Many genes summarized (TSC1/TSC2, ACADVL, AIRE, CBS, DLAT, DLD, GALT, HADHA, HEXA, IVD, NSD1 and others) are associated with disorders that typically present in childhood; the document notes these genes are generally not tested in the Medicare population.

Testing in older adult Medicare population is not generally indicated per OIG citation in the text.

Applicability and specific coverage considerations

Guidance regarding testing utility in the Medicare population:

Genes generally not indicated for routine testing in Medicare-aged patients: For genes where the associated diseases typically manifest in childhood or early life, molecular testing would not generally be performed in the Medicare population (predominantly ≥65 years).

Examples: NSD1, PAH, PDHA1, PTPN11, RET (HSCR), SLC9A6, SOS1, TAZ, UBE3A and many genes listed for CPT 81407/81408.

PRKAG2 billing restriction: PRKAG2 gene testing billed with a high level tier 2 code (e.g., 81406) is not supported.

[[chunk 113]]

RET mosaicism and parental testing: Molecular investigation of parents and multi-tissue testing may be essential to determine recurrence risk when RET mosaicism is suspected in Hirschsprung disease families; targeted family testing is preferred over routine population testing.

Supports targeted family testing rather than routine population testing.

CPT codes 81407 (Tier 2, level 8) and 81408 (Tier 2, level 9) for molecular pathology procedures are designated as noncovered in this policy and therefore are not covered for Medicare Advantage members when billed as Tier 2 molecular pathology procedures. Providers should select an appropriate alternative CPT code when a covered test/level applies and follow payer coding guidance.

Diagnosis codes listed in the policy's Non-Covered Diagnosis Codes List are never covered when submitted as the primary reason for the test. If such a code is used as the primary diagnosis, an Integrated Denial Notice (IDN) must be issued to the member and provider prior to rendering or referring for the service.

Within the segments cited here there are no additional explicit coverage exclusions beyond those already stated elsewhere in the policy. Providers should refer to the specific coding and not-covered lists in the policy for explicit exclusions.

The policy concludes that, for multiple individual Tier 2 genetic tests reviewed in this section, the available clinical evidence is of low quality or otherwise insufficient to demonstrate that testing directly impacts therapeutic decision-making, treatment, outcomes, or clinical management in the Medicare population; therefore coverage is not supported on the basis of improved health outcomes for those individual tests unless additional justification is provided.

Single-gene analyses for specific genes cited in the evidence review—examples include FKRP, SLC25A4, and MPZ—are described as having limited or insufficient published evidence of clinical utility in the Medicare population. As presented, single-gene testing for these genes is not supported as routinely covered without documentation demonstrating medical necessity and expected impact on management.

The policy notes that many genes (for example, TSC1/TSC2, ACADVL, CBS, GALT, HADHA, HEXA, IVD, NSD1 and others) are associated with disorders that typically manifest in childhood. Testing for these pediatric-onset conditions is generally not indicated for the Medicare-aged population and therefore is not routinely performed or covered for beneficiaries aged ≥65 unless there is clear clinical justification.

Testing for certain genes billed at a high-level Tier 2 CPT code is specifically not supported. For example, PRKAG2 testing billed with a high-level Tier 2 code (e.g., 81406) is not supported; similarly, the policy states that some F8 testing billed with high-level Tier 2 codes is not supported. Such billing may be denied and documentation of coding rationale is required when high-level Tier 2 codes are used.

For 21-hydroxylase congenital adrenal hyperplasia (CAH), the policy states that molecular genetic analysis is not essential to make the diagnosis but may be helpful in uncertain cases to confirm the basis of the defect and to aid genetic counseling. Molecular testing for CAH is therefore not required for diagnosis in routine cases but may be considered when clinically indicated.

Applicable diagnosis code Z83.72 was added to the policy's Non-Covered Diagnosis Codes List (see Policy History / Revision Information). When Z83.72 is submitted as the primary diagnosis for a molecular pathology test, the service is not covered.

The policy provides enumerated lists of individual genes and gene-groupings for which testing is considered unlikely to impact therapeutic decision-making in Medicare beneficiaries; tests for these genes will generally be denied as not reasonable and necessary unless there is strong, test-specific clinical justification. Examples span multiple CPT codes and include many genes listed across the non-covered lists.

When services are billed with a primary diagnosis from the explicit Non-Covered Diagnosis Codes List, the service is not covered and the provider must ensure an Integrated Denial Notice (IDN) is issued to the member and provider prior to rendering or referring for the service. This is a required step when collecting payment would otherwise be pursued for a non-covered primary diagnosis.

In the document segments referenced here there are no explicit statements using the phrase 'not medically necessary' beyond the gene- and diagnosis-based lists and narrative conclusions about insufficient evidence; the policy instead describes specific genes, coding guidance, and non-covered diagnosis codes that drive coverage decisions.

Covered Indications and When Testing Is Appropriate

Gene examples under certain CPT codes considered reasonable and necessary to guide therapeutic decision-making (e.g., CDKN2A, FGFR2/3, MEN1, RET, VHL, ATP7B, RYR1).

Example genes under Tier 2 codes: Examples of genes and contexts considered reasonable and necessary to guide therapeutic decision-making include CDKN2A, FGFR2/FGFR3 (erdafitinib candidacy), MEN1, RET, VHL, ATP7B (Wilson disease), and RYR1 (malignant hyperthermia susceptibility)

[[chunk 9]] [[chunk 11]] [[chunk 54]] [[chunk 55]] [[chunk 39]]

Gene-specific testing examples (FGFR2/3, RET, RYR1, ATP7B) associated with specified diagnoses

Gene–diagnosis pair examples: FGFR2/FGFR3 tumor profiling for metastatic urothelial carcinoma to identify erdafitinib candidates; RET testing associated with medullary thyroid carcinoma/MEN syndromes; RYR1 testing in contexts of anesthetic adverse events; ATP7B testing in suspected Wilson disease

[[chunk 18]] [[chunk 19]] [[chunk 39]] [[chunk 11]]

Coding, CPT/ICD Cross-References, and Non-Covered Diagnosis Codes

Tier 2 CPT CodesCPT

81400	Molecular pathology procedure, Level 1 (short description)
81401	Molecular pathology procedure, Level 2 (short description)
81402	Molecular pathology procedure, Level 3 (short description)
81403	Molecular pathology procedure, Level 4 (short description)
81404	Molecular pathology procedure, Level 5 (short description)
81405	Molecular pathology procedure, Level 6 (short description)
81406	Molecular pathology procedure, Level 7 (short description)
81407	Molecular pathology procedure, Level 8 (short description)
81408	Molecular pathology procedure, Level 9 (short description)

Examples of CPT/ICD cross-references includedmixed

81404	CPT Code 81404 for FGFR2, FGFR3
C67.0	Malignant neoplasm of trigone of bladder
C67.1	Malignant neoplasm of dome of bladder
C67.2	Malignant neoplasm of lateral wall of bladder
C67.3	Malignant neoplasm of anterior wall of bladder
C67.4	Malignant neoplasm of posterior wall of bladder
C67.5	Malignant neoplasm of bladder neck
C67.6	Malignant neoplasm of ureteric orifice
C67.7	Malignant neoplasm of urachus
C67.8	Malignant neoplasm of overlapping sites of bladder

1–10 of 13

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Applicable CPT/ICD Codes (excerpt)mixed

81404	FGFR2, FGFR3
81406	RYR1
C67.0	Malignant neoplasm of trigone of bladder
C67.1	Malignant neoplasm of dome of bladder
C67.2	Malignant neoplasm of lateral wall of bladder
C67.3	Malignant neoplasm of anterior wall of bladder
C67.4	Malignant neoplasm of posterior wall of bladder
C67.5	Malignant neoplasm of bladder neck
C67.6	Malignant neoplasm of ureteric orifice
C67.7	Malignant neoplasm of urachus

1–10 of 23

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Applicable CPT/ICD Codes (continued)mixed

81404	RET - MEN Type 2 (also 81405 referenced)
81405	RET - MEN Type 2
C73	Malignant neoplasm of thyroid gland
C74.10	Malignant neoplasm of medulla of unspecified adrenal gland
C74.11	Malignant neoplasm of medulla of right adrenal gland
C74.12	Malignant neoplasm of medulla of left adrenal gland
C75.0	Malignant neoplasm of parathyroid gland
D35.1	Benign neoplasm of parathyroid gland
81406	ATP7B
E83.01	Wilson's disease

Non-Covered Diagnosis CodesICD-10Not Covered

No codes listed

MolDx billing/coding entries (retired)mixed

A53562	Billing and Coding: MolDX: STAT3 Gene Testing; Retired 04/24/2024
A55209	Billing and Coding: MolDX: STAT3 Gene Testing; Retired 05/30/2024

Unsupported Tier 2 CPT Codes for specific genesCPTNot Covered

81406	Tier 2 molecular pathology procedure — high-level
81407	Tier 2 molecular pathology procedure — high-level

Tier 2 CPT Codes and examplesCPT

81407	Tier 2 individual genetic tests — level 8
81408	Tier 2 individual genetic tests — level 9
81406	High level Tier 2 code example referenced as not supported for PRKAG2

Provider Responsibilities, Prior Authorization, and Documentation

Billing Rule

Code selection and NOC requirement — Tier 2 molecular pathology

Use the appropriate Tier 2 molecular pathology CPT code for the analyte being tested. When the specific gene or analyte is not listed by an existing CPT code, use a Not Otherwise Classified (NOC) code and include supporting documentation explaining why a listed code does not apply.

Use analyte-specific Tier 2 CPT codes when available.
If analyte/gene is not listed, bill an appropriate NOC code and include justification.

Prior Authorization

Prior authorization may apply to gene-specific CPT codes

Prior authorization may be required for certain gene-specific CPT codes. Follow UnitedHealthcare prior authorization rules and any delegated utilization management requirements for Medicare Advantage members. Obtain prior authorization when required before performing testing to avoid claims denials or member liability.

Eligibility Requirements and Patient Selection

No top-level eligibility requirement nodes are present in these chunks. Refer to the coverage criteria and clinical indications sections for test-specific eligibility guidance.

No top-level eligibility requirement nodes are present in these chunks. See the detailed coverage criteria for applicable clinical and documentation requirements.

No top-level eligibility requirement nodes are present in these chunks. Eligibility determination depends on the clinical criteria and prior testing considerations described elsewhere in the policy.

No top-level eligibility requirement nodes are present in these chunks. Providers should follow the Medicare reasonable-and-necessary criteria when determining eligibility.

No top-level eligibility requirement nodes are present in these chunks. Documentation requirements and prior testing guidance are located in other sections of the policy.

No top-level eligibility requirement nodes are present in these chunks. Coverage is contingent on meeting the listed clinical validity, analytic validity, and impact-on-management criteria.

No top-level eligibility requirement nodes are present in these chunks. For tests not explicitly covered, prior authorization and additional documentation may be required.

No top-level eligibility requirement nodes are present in these chunks. See the policy's documentation and prior-auth sections for provider actions.

No top-level eligibility requirement nodes are present in these chunks. Clinical specialty guidance and family-history criteria inform test appropriateness.

Non-Covered Tests and Indications

The policy enumerates multiple individual genes and indications that are considered unlikely to impact clinical management for Medicare members and therefore will be denied as not reasonable and necessary when submitted without clear medical necessity. The lists include many genes grouped by CPT code and explicitly note that certain high-level Tier 2 billing for specific genes (e.g., F8, PRKAG2) is not supported. When those genes are listed or when Tier 2 level 8/9 coding is used inappropriately, claims may be denied.

Tests submitted with a primary diagnosis code from the policy's Non-Covered Diagnosis Codes List are not covered. The policy was updated to add Z83.72 to that list (05/01/2025); when such a non-covered primary diagnosis is used, an Integrated Denial Notice (IDN) is required prior to rendering or referring for the service.

In the chunks cited here, there are no additional explicit test exclusions beyond the gene-specific lists and non-covered diagnosis guidance; consult the full policy lists and coding tables for enumerated non-covered tests.

Multiple individual Tier 2 genetic tests reviewed in this section are summarized as having insufficient evidence of clinical utility in the Medicare population; coverage may not be supported for these tests unless stronger, test-specific evidence demonstrating impact on management is provided.

Testing for FKRP, SLC25A4, and MPZ is described as having limited or insufficient evidence of clinical utility in the Medicare population. As a result, single-gene testing for these genes is not supported as routinely covered without additional clinical justification and documentation.

Background, Definitions, and Context

Background: Molecular pathology procedures analyze nucleic acid variants to detect germline or somatic alterations and can include HLA typing. Tier 2 procedures represent tests generally performed in lower volumes and for rarer conditions; Tier 2 CPT codes are arranged by increasing levels of technical resources and interpretive physician work.

Tier 2 molecular pathology procedures

DefinitionTier 2 molecular pathology procedures are tests performed at lower volumes than Tier 1, arranged by increasing levels of technical resources and interpretive physician work for rarer conditions

Context for code selectionUse the specific molecular pathology procedure level code that includes the analyte; if the analyte/gene is not listed under Tier 2 or Tier 1 codes, assign the Not Otherwise Classified (NOC) CPT code

Relation to NGS/panelsTier 2 individual biomarker CPT codes should not be used when testing is performed as part of NGS or other multiplexing technology panels

Typical useOften used for rare disease testing or specialized analyses where analytic and interpretive effort is higher

Counseling, Referral, and Specialist Involvement

Documentation Required

Use multidisciplinary teams and genetic counseling for syndromic/hereditary diagnoses

Manage patients and families with multidisciplinary teams and provide genetic counseling when syndromic diagnoses or hereditary cancer syndromes are suspected, per guideline recommendations.

MEN1 and VHL care is recommended via multidisciplinary teams; consider referral to relevant specialists.
Document counseling and multidisciplinary referrals when ordering genetic testing for syndromic conditions.

Documentation Required

Recommend genetic counseling when ClinGen actionability or variant interpretation affects management

Offer genetic counseling when ClinGen actionability or gene-specific variant interpretation affects management (examples include ATP7B/Wilson disease and RYR1/malignant hyperthermia).

ClinGen has strong actionability assertions for ATP7B and RYR1; counseling is important where results would change management.
Document counseling offered or provided in the medical record.

Policy Updates and Revision History

Policy Summary

PayerUnitedHealthcare

PolicyTier 2 Molecular Pathology Procedures

Policy CodePolicy MMP381.22

Change TypeMaterial updates to Non‑Covered Diagnosis Codes and policy versioning

Effective DateMay 1, 2025

Next Review DateN/A

Key ActionUse the appropriate Tier 2 molecular pathology CPT code and provide documentation showing alternative tests are unavailable or equivocal and that results will directly impact management.

SourceLink

On This Page

DLAT / PDHC-related genes: DLAT evidence is currently insufficient to support clinical use; PDHA1 is the most common gene associated with pyruvate dehydrogenase complex deficiency; molecular testing approaches include gene-targeted panels or comprehensive genomic testing.

DLAT accounts for small percentage (1-4%) of PDHC cases; clinical utility not established.

F8 gene testing billed with high-level Tier 2 CPT codes is not supported.

Billing/coding coverage restriction (see coding module).

NSD1 / Sotos syndrome: NSD1 pathogenic variants cause Sotos syndrome with modestly increased cancer risk; implications discussed but prospective studies recommended and no specific additional coverage criteria provided.

Clinical implications discussed but no specific coverage criteria provided.

Evaluation for hereditary cancer syndromes — testing appropriate with personal/family history (e.g., CDKN2A, RET)

Hereditary cancer evaluation: Genetic testing is appropriate for individuals with personal or family histories suggestive of hereditary cancer syndromes (e.g., CDKN2A in melanoma/pancreatic cancer families; RET for medullary thyroid carcinoma), and can reclassify apparent sporadic cases to hereditary diagnoses

[[chunk 37]] [[chunk 49]] [[chunk 131]]

Tumor profiling for FGFR2/3 in metastatic urothelial carcinoma to identify candidates for erdafitinib after chemotherapy progression

FGFR2/3 tumor profiling for erdafitinib: Tumor profiling for FGFR2/3 mutations or fusions in metastatic urothelial carcinoma is appropriate to identify candidates for erdafitinib after progression on chemotherapy

[[chunk 39]] [[chunk 18]]

Testing for PRSS1 in early-onset or familial pancreatitis

PRSS1 testing in pancreatitis: Testing for PRSS1 is reasonable in early-onset or familial pancreatitis to inform risk and surveillance, recognizing it does not precisely predict penetrance

[[chunk 43]] [[chunk 44]] [[chunk 124]]

ATP7B (Wilson disease) and RYR1 (malignant hyperthermia) have ClinGen strong actionability assertions

ClinGen strong actionability examples: ATP7B (Wilson disease) and RYR1 (malignant hyperthermia susceptibility) have ClinGen 'strong' actionability assertions and are highlighted as clinically actionable gene–disease pairs

[[chunk 54]] [[chunk 55]] [[chunk 126]] [[chunk 127]]

Hearing impairment or combined hearing and visual impairment where Usher syndrome is suspected — molecular screening supported

Usher suspicion with hearing impairment: Hearing impairment or combined hearing and visual impairment where Usher syndrome is suspected—molecular screening is supported to identify individuals at high risk for retinitis pigmentosa

[[chunk 72]]

Clinical presentation and neurophysiology consistent with CMT — sequential testing recommended

CMT clinical presentation and testing sequence: Clinical presentation and neurophysiology consistent with CMT: start with clinical assessment and neurophysiological study; perform PMP22 duplication testing first for demyelinating or undetermined forms, then NGS panel and CNV analysis as indicated

[[chunk 90]] [[chunk 122]]

Vestibular schwannoma or clinical suspicion of NF2 — NF2 testing relevant

NF2 indications: Vestibular schwannoma or clinical suspicion of NF2—NF2 testing is relevant; include MRI with gadolinium and relevant clinical signs in the workup

[[chunk 91]] [[chunk 90]]

Suspected CMT with demyelinating or undetermined neurophysiology — PMP22 duplication then NGS panel and CNV analysis

CMT testing sequence (suspected demyelinating/undetermined): Suspected CMT with demyelinating or undetermined neurophysiological findings: perform PMP22 duplication testing first; if negative proceed to NGS panel including listed genes and CNV analysis

[[chunk 90]]

Vestibular schwannoma (VS) evaluation — MRI with gadolinium is gold standard; NF2 alterations implicated

VS evaluation and NF2 relevance: Vestibular schwannoma evaluation: MRI with gadolinium is gold standard; NF2 alterations implicated in sporadic and NF2-associated VS and may have implications for tumor biology and future targeted approaches

[[chunk 91]]

Wilson disease (ATP7B testing) — AASLD recommends ATP7B testing when diagnosis uncertain and for targeted relative testing

ATP7B (Wilson disease) testing: ATP7B testing is recommended by AASLD when available for patients in whom diagnosis is uncertain and for targeted analysis in first-degree relatives

[[chunk 126]] [[chunk 54]]

Hereditary neuropathy evaluation — guideline support for genetic testing (AAN/AANEM/AAPMR)

Hereditary neuropathy testing: Genetic testing for diagnosis and classification of hereditary neuropathies is supported by AAN/AANEM/AAPMR and may be considered in cryptogenic polyneuropathy with classic phenotype

[[chunk 122]]

VHL risk evaluation — genetic testing for pathogenic VHL variants when risk present

VHL risk evaluation: Patients at risk of VHL disease (ocular findings or first-degree relatives) should undergo genetic testing for pathogenic VHL variants as part of evaluation

[[chunk 123]]

Idiopathic chronic pancreatitis — evaluate for PRSS1 and related genes

Idiopathic chronic pancreatitis testing: Evaluate for PRSS1, SPINK1, CFTR, and CTRC mutation analysis in idiopathic chronic pancreatitis per ACG guidance

[[chunk 124]]

PAH genotyping — indicated following newborn screening/biochemical workup for PAH deficiency

PAH genotyping is indicated following newborn screening and biochemical workup for PAH deficiency to inform therapy planning

[[chunk 125]]

Malignant hyperthermia susceptibility (RYR1/CACNA1S) — pathogenic variants diagnostic; relevant to anesthetic planning

Malignant hyperthermia susceptibility testing: Pathogenic variants in RYR1 or CACNA1S establish malignant hyperthermia susceptibility and are diagnostic; genetic results are relevant to anesthetic planning and DNA screening is an accepted alternative to IVCT/CHCT in guideline statements

[[chunk 127]] [[chunk 128]]

Diagnostic evaluation when Wilson disease uncertain or for first-degree relative testing

Wilson disease diagnostic evaluation: When Wilson disease diagnosis is uncertain or for targeted testing of first-degree relatives, ATP7B testing is recommended if available

[[chunk 126]]

Assessment of malignant hyperthermia susceptibility — DNA screening context referenced

Assessment of malignant hyperthermia susceptibility: DNA screening for malignant hyperthermia susceptibility is recognized as a viable diagnostic approach and may be used in assessment of at-risk individuals

[[chunk 127]] [[chunk 128]]

Tumor/somatic molecular profiling for advanced or metastatic cancer — NCCN-recommended/considered testing in CLIA labs

Tumor/somatic molecular profiling contexts: Tumor/somatic molecular profiling for advanced or metastatic cancer stages is recommended or considered by NCCN in CLIA-approved laboratories to identify actionable alterations or trial eligibility

[[chunk 130]] [[chunk 131]] [[chunk 132]]

Germline testing for hereditary cancer syndromes per NCCN criteria (RET, CDKN2A, pancreatic genes)

Germline testing per NCCN: Germline testing for hereditary cancer syndromes (e.g., RET, CDKN2A, pancreatic cancer susceptibility genes) is appropriate per NCCN criteria and genetic counseling is recommended when pathogenic variants are identified

[[chunk 131]] [[chunk 130]]

Check payer- or delegate-specific prior authorization policies for gene-specific CPT codes (e.g., some FGFR, RET, RYR1 listings).
For Medicare Advantage members with delegate-managed utilization, follow the delegate's prior authorization process.

Billing Rule

Prior authorization note — F8 Tier 2 codes not supported

F8 (Coagulation Factor VIII) gene testing billed with a high-level Tier 2 code (for example, 81406 or 81407) is not supported. Billing at an unsupported high-level Tier 2 code may lead to denial.

Do not bill F8 testing with high-level Tier 2 CPT codes (e.g., 81406, 81407).
Select the correct CPT level consistent with the test complexity and payer guidance.

Prior Authorization

Prior authorization for guideline-recommended tumor testing

Follow NCCN and other guideline-based recommendations for tumor/somatic molecular testing. When NCCN recommends or considers molecular/genomic testing for a given cancer stage, obtain prior authorization if required and document the tumor stage and clinical rationale on the request and claim.

Document tumor stage and why results would affect treatment decisions (e.g., bladder, melanoma, thyroid, uveal, metastatic disease).
Obtain prior authorization when payer rules require it for guideline-recommended tumor/genomic testing.

Denial Risk

Non-covered primary diagnosis triggers denial — IDN requirement

If the primary diagnosis code for the test is on the Non-Covered Diagnosis Codes List, the service is never covered. Before rendering or referring for a non-covered service, call UnitedHealthcare to issue an Integrated Denial Notice (IDN) and confirm the member has received the IDN prior to collecting payment.

Non-covered primary diagnoses always trigger denial for the service.
You must ensure the member receives the IDN prior to rendering or referring for the non-covered service to collect payment.

Billing Rule

Billing/coding retired guidance

Be aware of retired MolDx billing and coding guidance that may have been referenced historically. Retired entries (e.g., STAT3 billing guidance) may affect how prior guidance is interpreted; follow current UnitedHealthcare and MolDx resources.

Retired MolDx billing/coding documents (see Palmetto MolDx notices) may appear in historical references but are no longer current guidance.
Confirm current coding/billing guidance with UnitedHealthcare or MolDx resources before billing.

Denial Risk

Insufficient evidence may trigger denial

Insufficient clinical evidence or lack of demonstrated clinical utility for many Tier 2 tests may lead to denial. Ensure the requested test has analytic validity and clinical utility supported by peer-reviewed literature and that results will directly impact treatment or management.

Tests with low or insufficient evidence for clinical utility (examples noted in policy) are at risk of denial.
When evidence is limited, include strong clinical justification and references to peer-reviewed literature.

Denial Risk

VWF genetic testing — low impact on management

VWF gene testing is unlikely to impact clinical management in many cases because standard coagulation testing and clinical presentation often suffice to diagnose and guide treatment. Reserve VWF genetic testing for cases where genetic information would change management.

Do not routinely order Tier 2 VWF testing when clinical and standard lab studies suffice.
If ordering VWF genetic testing, document why genetic results are expected to change management.

Billing Rule

Unsupported high-level Tier 2 billing for F8

Do not bill F8 testing with unsupported high-level Tier 2 CPT codes (e.g., 81406/81407). Such billing is not supported and may result in claim denial.

Select the appropriate CPT code level for F8 testing per payer guidance; avoid high-level Tier 2 codes that are not supported.

Prior Authorization

Guideline-recommended tumor/genomic testing

Guideline-recommended tumor and genomic testing should be performed when results could inform targeted therapy or trial eligibility. When testing is indicated by guidelines (e.g., NCCN), document stage, intended clinical use of results, and obtain prior authorization when required.

Perform tumor/somatic profiling when actionable alterations may affect therapy selection or trial eligibility.
Document intended treatment implications or clinical trial considerations on prior authorization requests and claims.

Documentation Required

Required documentation — demonstrate necessity and validity

Required documentation must show that alternative tests are unavailable or equivocal, that the test has analytic and clinical validity, and that results will directly affect treatment or management. For panel tests, document why the selected genes are necessary and limit testing to genes reasonable and necessary to establish a diagnosis.

Document that alternative laboratory or clinical tests are unavailable or equivocal.
Provide evidence of analytic validity (e.g., CLIA/LDT/FDA status) and peer-reviewed literature supporting clinical utility.
For panels, justify the number of genes/tests ordered and that prior single-gene testing has not already provided diagnosis.

Documentation Required

Clinical justification and family history documentation

Document clinical justification including personal and family history that supports genetic testing. Include family history details, recurrence-risk considerations (e.g., parental testing for RET-related Hirschsprung disease), and prior testing history.

Provide relevant family history and explain how results will impact management or recurrence risk counseling.
When parental molecular investigation is required (e.g., RET/HSCR), include parental testing rationale.

Documentation Required

Supporting documentation expectations

Include supporting documentation expectations: provide clinical assertions, relevant laboratory/imaging results, and literature references when available. For tests prone to variant reclassification, document the clinical context and prior testing to support the request.

Attach pertinent clinical notes, prior test results, and references to peer-reviewed evidence.
Explain how test results would alter clinical management given potential variant uncertainty.

Documentation Required

Clinical presentation documentation for Usher testing

For Usher syndrome testing, document the clinical presentation of hearing and/or visual impairment and the rationale for molecular screening. Indicate whether the patient has combined auditory and visual symptoms or isolated sensorineural hearing loss that justifies molecular testing.

Document presence of hearing loss and/or retinitis pigmentosa or risk thereof.
Include rationale for molecular screening and how results would guide surveillance or management.

Documentation Required

Imaging and clinical documentation for NF2 testing

For NF2 (vestibular schwannoma) testing, include imaging and clinical documentation such as MRI with gadolinium showing lesions in the internal auditory canal or cerebellopontine angle and relevant clinical signs. Document why molecular testing is needed and how results would impact management.

Attach MRI with gadolinium reports/images and clinical exam findings.
Explain how molecular results would influence surveillance, surgery, or targeted therapy decisions.

Step Therapy

Stepwise testing and sequencing recommendations for CMT

Follow a stepwise, guideline-based diagnostic sequencing for Charcot-Marie-Tooth (CMT). Begin with clinical assessment and neurophysiology, then perform targeted testing (e.g., PMP22 duplication) prior to broader NGS panels. Document each step in the diagnostic pathway.

Clinical assessment → neurophysiologic testing → targeted genetic testing (start with PMP22 duplication for demyelinating/undetermined forms).
If targeted testing is negative, proceed to appropriate NGS panel and document rationale for expanding testing.

Documentation Required

Prior clinical evaluation before broad testing

Before ordering broad or multi-gene testing, perform prior clinical evaluation and document that standard clinical evaluation and targeted tests have been completed or are inadequate. Broad testing should follow focused evaluation when multi-system surveillance or interventions are being considered (e.g., HNF1B).

Document prior clinical evaluations and why broader testing is indicated.
For multi-system disorders, show that targeted evaluations were performed and that broader panels are reasonably necessary.

Note

Therapy context for FGFR2/3 and other actionable alterations

Therapy context: For genes with actionable targeted therapies (e.g., FGFR2/3 in metastatic urothelial carcinoma treated with erdafitinib), document prior therapy history and how molecular results would affect therapeutic sequencing and choice of targeted agents.

Include prior treatment history (chemotherapy, immunotherapy) when ordering testing to support therapy choice.
Document intended use of results to select targeted therapy or enrollment in clinical trials.

Note

Claims submission responsibility and delegation

Providers are responsible for accurate claims submission using applicable CPT and CMS coding guidelines. For Medicare Advantage members with delegated utilization management, follow the delegate's prior authorization and documentation requirements.

Submit accurate claims and ensure documentation supports medical necessity.
Follow delegate requirements where utilization management is delegated.

No top-level eligibility requirement nodes are present in these chunks. Eligibility is assessed against the Medicare reasonable-and-necessary criteria in the policy.

No top-level eligibility requirement nodes are present in these chunks. Providers must document that alternative diagnostic tests are unavailable or equivocal when applicable.

No top-level eligibility requirement nodes are present in these chunks. For tumor testing that is guideline-recommended, obtain appropriate prior authorization when required by benefit design.

The policy specifically states that F8 gene testing billed with high-level Tier 2 molecular pathology CPT codes (for example, 81406, 81407) is not supported and may be denied when billed at those levels.

The policy indicates that DLAT testing currently lacks sufficient peer‑reviewed published evidence to support clinical utility; additional studies are necessary before clinical use can be recommended for Medicare members.

The policy states that PRKAG2 gene testing billed with a high-level Tier 2 code (for example, 81406) is not supported. Such billing may be denied and providers should code and justify testing consistent with policy guidance.

No explicit test exclusions are listed for CAH in these chunks; rather, molecular genetic analysis for 21-hydroxylase CAH is characterized as not essential for routine diagnosis but potentially helpful in uncertain cases. The policy does not list CAH molecular testing as categorically excluded.

Diagnosis code Z83.72 has been identified in the policy as a non-covered diagnosis code in the Policy History/Revision Information (effective 05/01/2025). Services billed with Z83.72 as the primary diagnosis are not covered.

Full gene sequencing reporting

Reporting ruleFull gene sequencing must be reported only with a CPT code whose descriptor explicitly states 'full gene sequence'—do not report full gene sequencing using variant-targeted codes

Code selection implicationAssign the CPT code described as 'full gene sequence' only when the assay performed was a full gene sequence

Panel considerationsWhen additional variants beyond those listed for a code are tested, they are included in the procedure and not reported separately—select the code that matches the assay performed

Integrated Denial Notice (IDN)

DefinitionIntegrated Denial Notice (IDN) is a notice issued to the member and provider informing the member of liability for a non-covered service and their appeal rights

Timing requirementThe IDN must be provided to the member prior to rendering or referring for non-covered services or items

Provider actionIf a primary diagnosis is on the Non-Covered Diagnosis Codes List, call UnitedHealthcare to ensure an IDN is issued before collecting payment

ClinGen Actionability Assertion

DefinitionClinGen Actionability Assertion is a semi-quantitative, metric-based assertion of clinical actionability for a gene–condition pair indicating potential for prevention, early detection, or management changes when a pathogenic variant is identified

Scoring componentsClinGen SQM summarizes severity, likelihood, effectiveness of interventions, nature of intervention, and state of the knowledge base

UseClinGen actionability summaries guide analysis and reporting of genomic variation and help identify disorders with greater clinical utility when identified in previously undiagnosed adults

Clinical actionability (ClinGen/SQM)

DefinitionClinical actionability (ClinGen/SQM) describes a clinically prescribed intervention specific to a genetic disorder that is effective for prevention or delay of clinical disease, lowering clinical burden, or improving outcome in a previously undiagnosed adult

ScopeActionability includes patient management and interventions to improve outcomes for at-risk family members, though family testing alone does not meet actionability criteria

BasisScored using ClinGen's Semi-quantitative Metric considering effectiveness and evidence supporting interventions

ACMG/AMP variant classification specifications — example (RYR1)

DefinitionACMG/AMP variant classification specifications are gene-specific adjustments to the ACMG/AMP pathogenicity criteria to improve accuracy of variant classification for a given gene–disease pair

ExampleFor RYR1 (malignant hyperthermia), the ClinGen Expert Panel modified several ACMG/AMP criteria (some adopted unchanged, some with gene-specific modifications, others dropped) and calibrated quantitative evidence using likelihood ratios

PurposeGene-specific specifications facilitate more accurate curation and interpretation of variants, including secondary findings reporting

Usher genes / usherome

DefinitionUsher genes (the 'usherome') are a group of genes (e.g., USH2A, MYO7A, CDH23, ADGRV1, PCDH15, USH1C, CLRN1, USH1G, WHRN, PDZD7, CIB2) associated with combined hearing loss and retinitis pigmentosa; biallelic pathogenic variants confer high RP risk

EpidemiologyIn cohorts of patients with combined visual and hearing impairment, USH2A accounts for ~50% of biallelic mutations; in isolated sensorineural deafness ~7.5% had disease-causing Usher gene mutations

Testing implicationAuthors recommend early molecular screening in deaf children to identify those at high risk for RP

PMP22 duplication

DefinitionPMP22 duplication is a recurrent copy-number change accounting for many demyelinating Charcot–Marie–Tooth (CMT) cases

Role in testingPMP22 duplication testing is recommended as first-line genetic testing in patients with demyelinating or undetermined neurophysiological forms prior to broader NGS panel testing

Testing approachIf PMP22 duplication is negative, proceed to NGS panel including CMT-associated genes and consider CNV analysis as indicated

CMT diagnostic sequence

Recommended sequenceCMT diagnostic sequence: clinical assessment → neurophysiological study → genetic testing beginning with PMP22 duplication testing for demyelinating/undetermined forms, then NGS panel and CNV analysis as indicated

Panel contentRecommended NGS panel genes include GJB1, MPZ, PMP22, SH3TC2, MFN2, GDAP1, MME, HSPB1; consider sequencing of GJB1, SORD, MT-ATP6 and CNV analysis in other genes

RationaleConsensus guideline supports a stepwise approach to maximize diagnostic yield and limit unnecessary broad testing

Gold standard for vestibular schwannoma diagnosis

Gold standard testMRI with gadolinium focused on the internal auditory canal and pontocerebellar angle is the gold standard for vestibular schwannoma diagnosis; histological confirmation is not required due to high sensitivity and specificity

Clinical implicationInclude MRI findings when seeking NF2-related genetic testing for vestibular schwannoma or NF2 suspicion

Molecular relevanceNF2 inactivation is a driver of VS and NF2 alterations are also found in other tumors (e.g., ≥10% prevalence in a mesothelioma cohort), supporting molecular evaluation in appropriate contexts

Malignant hyperthermia susceptibility (MHS)

DefinitionMalignant hyperthermia susceptibility (MHS) is a clinical susceptibility diagnosed by either a positive in vitro muscle contracture test (IVCT/CHCT) or the presence of a pathogenic variant in RYR1 or CACNA1S detected by molecular genetic testing

Clinical triggerExposure to potent volatile anesthetics or succinylcholine can trigger a malignant hyperthermia reaction in susceptible individuals

Implication for careIdentification of pathogenic variants in RYR1 or CACNA1S is relevant for anesthetic planning and is included among genes for return of secondary findings

Malignant hyperthermia susceptibility (MHS) — genes and criteria

Diagnostic criteriaMHS diagnosis can be established by a positive IVCT/CHCT muscle bioassay or by presence of a pathogenic variant in RYR1 or CACNA1S on molecular testing

Guideline recognitionCPIC and European Malignant Hyperthermia Group accept pathogenic variants in RYR1 or CACNA1S as diagnostic; DNA-based screening is considered a viable alternative to contracture testing

Secondary findings noteACMG includes RYR1 and CACNA1S on the list of genes for which pathogenic variants should be returned as secondary findings

Wilson disease (WD)

DefinitionWilson disease (WD) is a genetic disorder of copper metabolism associated with ATP7B dysfunction

Diagnostic componentsDiagnostic criteria include Kayser–Fleischer (KF) rings, low serum ceruloplasmin, liver copper quantification and, when available, ATP7B genetic testing to confirm diagnosis or evaluate relatives

Use of genetic testingAASLD recommends ATP7B testing if available for patients where diagnosis is uncertain and for targeted analysis in first-degree relatives

Clinical literature supporting testing indications and interpretation

ReferencesPolicy cites multiple peer-reviewed references supporting testing indications and interpretation, including consensus guidelines, systematic reviews, and gene-specific studies (see reference list)

Types of literatureCited literature includes clinical practice guidelines (e.g., AAN/AANEM, AAO, AASLD, NCCN), systematic reviews, cohort studies, and gene-specific expert-panel reports

PurposeReferences inform clinical validity, actionability assessments, and gene-specific interpretation guidance used in coverage rationale

Documentation Required

Provide genetic counseling for conditions with prognostic or family implications (Usher, CMT)

Provide or refer for genetic counseling when testing has implications for prognosis or family risk (for example Usher syndrome and CMT), and document counseling in the record.

Usher testing has implications for ophthalmologic risk; CMT has family and prognostic implications—counseling is implied although not mandated in this section.
Record counseling discussions and family planning implications when testing is ordered.

Documentation Required

Counsel families when pursuing parental/familial molecular testing (e.g., RET mosaicism)

When parental or familial molecular testing is pursued (for example to assess RET mosaicism), provide genetic counseling to explain recurrence risk and implications for family members.

Jiang et al. recommend parental multi-tissue investigation for RET mosaicism; counseling should accompany familial testing.
Document counseling and the informed consent process for parental/familial testing.

Documentation Required

Refer to specialists/multidisciplinary teams for syndromic diagnoses (e.g., MEN1, VHL)

Refer patients to relevant specialists or multidisciplinary teams for syndromic diagnoses (examples: MEN1, VHL) and document specialist involvement when ordering genetic testing.

Multidisciplinary panels are recommended for complex syndromic conditions; involve appropriate specialties and record referrals.
Specialist involvement supports the clinical rationale for testing and may be required for coverage review.

Documentation Required

Include specialty involvement where clinically relevant (e.g., anesthesiology for RYR1)

Consider specialty context when ordering gene tests (for example anesthesiology input for RYR1/MH risk, nephrology for AQP2/AVPR2 work-up) and document the clinical specialty involvement.

Anesthesiologists should insist on RYR1 genetic work-up in patients with recurrent rhabdomyolysis or congenital myopathies prior to exposure to triggering anesthetics.
Document specialty consultations that support the decision to order the genetic test.

Documentation Required

Specialist context implied for ordering; document specialty involvement (Usher, CMT)

Ordering is generally implied by specialist involvement (for example audiology/ENT for Usher, neurology/genetics for CMT); although no specific ordering provider limitations are stated, document the specialist context when appropriate.

Policy implies specialists typically direct testing for condition‑specific indications; documenting the specialty context supports medical necessity.
No explicit restriction on which provider may order testing is provided here.

Note

No specific ordering provider limitations stated; follow clinical and guideline context

The policy does not restrict which provider types may order testing; recommendations reference guideline-based testing and genetic counseling but do not mandate specific ordering provider limitations.

Clinical context and guideline citations imply specialist-directed testing in many cases, but no explicit ordering provider limits are stated.
Document clinical justification and specialty consultations when ordering tests.