Molecular Analysis of Solid Tumors and Hematologic Malignancies — Coverage Criteria
Governs somatic molecular genomic profiling (tumor and hematologic) to identify actionable driver mutations for diagnosis, prognosis, and treatment selection; affects providers ordering tumor-based testing and laboratories performing these tests.
Policy Summary
PayerCentene
PolicyMolecular Analysis of Solid Tumors and Hematologic Malignancies — Coverage Criteria
Policy CodePolicy N/A
Change TypeNo material change
Effective DateN/A
Next Review DateN/A
Key ActionOrder guideline-recommended molecular testing when results will guide therapy and document counseling for potential incidental germline findings.
Repeat testing considered medically necessary when ANY of the following progression conditions are met
Repeat testing progression list: 1. Metastatic colon cancer OR 2. Advanced or metastatic non-small cell lung cancer (NSCLC) OR 3. Advanced or metastatic gastric adenocarcinoma OR 4. Metastatic prostate cancer OR 5. Ovarian cancer that is platinum-sensitive
Applies to listed tumor-type agnostic panel codes
inv-03: Tumor-type agnostic panels with IHC and cytogenetic analyses
Covered when ALL of the following are met
Panel with IHC/cytogenetics initial use: A. Member has recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer
AND B: member is seeking further cancer treatment (for example, therapeutic chemotherapy)
Covered when ANY of the following are met (distinct indications listed A–D)
Hematologic panel indications: A. Blood work (CBC) and bone marrow evaluation consistent with acute myeloid leukemia (AML) OR B. Newly diagnosed myelodysplastic syndrome with persistent cytopenia(s) (at least 4–6 months) with other causes ruled out OR C. Suspected myeloproliferative neoplasm (initial evaluation or after negative JAK2/CALR/MPL) OR D. Diagnosis of chronic myelogenous leukemia (CML) with progression to accelerated/blast phase or after negative BCR-ABL1 kinase domain mutation analysis
If multigene panel is performed, appropriate panel codes should be used
Colorectal panel criteria: A. Suspected or proven metastatic, synchronous or metachronous colorectal cancer AND B. Member is seeking further cancer treatment (e.g., therapeutic chemotherapy) AND C. Either no prior somatic multigene testing for the same primary colorectal cancer OR prior somatic multigene testing was performed for a different primary and a new primary colorectal cancer diagnosis is present
If a panel is performed, appropriate panel codes should be used
Lung panel criteria: A. Diagnosis of advanced (stage IIIb or higher) or metastatic lung adenocarcinoma, large cell lung carcinoma, squamous cell lung carcinoma, or NSCLC NOS AND B. Member is seeking further cancer treatment (e.g., therapeutic chemotherapy)
Repeat testing is medically necessary when progression on targeted therapy for NSCLC
Melanoma panel criteria: A. New diagnosis of stage IV melanoma or recurrent melanoma AND B. Member is seeking further cancer treatment AND C. Either no prior somatic multigene testing for the same primary melanoma diagnosis OR prior somatic multigene testing exists but a new primary melanoma diagnosis is present
If a panel is performed, appropriate panel codes should be used
inv-08: AML-focused molecular profiling panels
Covered when ALL of the following are met
AML panel criteria: Member has a suspected or confirmed diagnosis of acute myeloid leukemia (AML)
If a multigene panel is performed, appropriate panel codes should be used
MPN panel criteria: A. Member is suspected to have a myeloproliferative neoplasm (polycythemia vera, essential thrombocythemia, primary myelofibrosis, or chronic myeloid leukemia) AND B. The panel does not include genes other than JAK2, CALR, MPL, and BCR/ABL1
MPN panels including other genes are investigational
inv-10: Tumor specific BCR/ABL kinase domain analysis
Covered when ALL of the following are met
BCR/ABL kinase domain analysis criteria: A. Diagnosis of chronic myeloid leukemia (CML) or Ph-like acute lymphocytic leukemia (ALL) AND B. Any of: inadequate initial response to TKI therapy, loss of response to TKI therapy, progression to accelerated/blast phase, or relapsed/refractory disease
inv-11: Tumor specific BCR/ABL1 quantitation and breakpoint analysis
Covered when ANY of the following are present
BCR/ABL1 quantitation indications: Suspected myeloproliferative neoplasm OR undergoing workup/monitoring for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), or B-cell lymphoma
inv-12: Tumor specific BRAF variant analysis
Covered when ANY of the following diagnoses are present
BRAF variant analysis indications: Suspected or proven metastatic, synchronous or metachronous colorectal cancer OR advanced/metastatic NSCLC OR stage III/IV cutaneous melanoma OR indeterminate thyroid nodules requiring biopsy OR anaplastic/advanced thyroid carcinomas OR low-grade glioma/pilocytic astrocytoma; additionally evaluation for hairy cell leukemia in specific immunophenotype context
inv-13: Tumor specific BRCA1/2 variant analysis
Covered when ANY of the following diagnoses are present
Tumor BRCA1/2 indications: A. Ovarian, fallopian tube, or primary peritoneal cancer OR B. Metastatic prostate cancer
Consider germline and somatic BRCA1/2 testing per guideline recommendations
inv-14: Tumor specific CALR variant analysis
Covered when the following is met
CALR variant analysis criteria: Member is suspected to have a myeloproliferative neoplasm
inv-15: Tumor specific CEBPA variant analysis
Covered when the following is met
CEBPA variant analysis criteria: Member has cytogenetically normal acute myeloid leukemia (AML)
inv-16: Tumor specific EGFR variant analysis
Covered when ANY of the following diagnoses are present
EGFR variant analysis indications: Advanced or metastatic lung adenocarcinoma OR advanced or metastatic large cell lung carcinoma OR advanced or metastatic squamous cell lung carcinoma OR advanced or metastatic non-small cell lung cancer (NSCLC) NOS
inv-17: Tumor Specific CEBPA Variant Tests — CEBPA
Covered when ALL of the following are met for CEBPA:
CEBPA criteria: Member has cytogenetically normal acute myeloid leukemia (AML)
inv-18: Tumor Specific EGFR Variant Analysis — lung diagnoses
Covered when ANY of the following lung diagnoses are present:
EGFR indications: Advanced or metastatic lung adenocarcinoma OR advanced or metastatic large cell lung carcinoma OR advanced or metastatic squamous cell lung carcinoma OR advanced or metastatic non-small cell lung cancer (NSCLC) NOS
inv-19: Tumor Specific ESR1 Variant Analysis
Covered when ALL the following are met for ESR1:
ESR1 indications: Postmenopausal female or adult male with ER-positive and HER2-negative breast cancer AND disease progression after one or two prior lines of endocrine therapy including one line containing a CDK4/6 inhibitor
inv-20: Tumor Specific FLT3 Variant Analysis
Covered when ANY of the following hematologic malignancy indications are present for FLT3:
FLT3 indications: Suspected or confirmed acute myeloid leukemia (AML) OR acute lymphocytic leukemia (ALL) OR myelodysplastic syndrome (MDS)
inv-21: Tumor Specific IDH1 and IDH2 Variant Analysis
Covered when ANY of the following are present for IDH1/IDH2:
IDH1/2 indications: Diagnosis of a glioma OR diagnosis of acute myeloid leukemia (AML)
inv-22: Tumor Specific IGHV Somatic Hypermutation Analysis
Covered when ANY of the following hematologic diagnoses are present for IGHV:
IGHV indications: Chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) OR primary cutaneous B-cell lymphoma OR mantle cell lymphoma OR post-transplant lymphoproliferative disorder
NCCN/ASCO guidance supports IGHV sequencing for prognostic/therapy determination
inv-23: Tumor Specific JAK2 Variant Analysis
Covered when ANY of the following are present for JAK2:
JAK2 indications: Suspected myeloproliferative neoplasm (e.g., PV, ET, primary myelofibrosis, CML) OR acute lymphoblastic leukemia (ALL) OR suspected myelodysplastic syndrome (MDS)
If JAK2 negative, test MPL and CALR or use multigene NGS panel including them per guidelines
inv-24: Tumor Specific KIT Variant Analysis
Covered when ANY of the following are present for KIT:
KIT indications: Suspected or being evaluated for systemic mastocytosis OR diagnosis of acute myeloid leukemia (AML) OR stage IV cutaneous melanoma OR suspected or confirmed gastrointestinal stromal tumor (GIST)
NCCN recommends KIT testing in GIST and stage IV melanoma
inv-25: Tumor Specific KRAS Variant Analysis
Covered when ANY of the following are present for KRAS (note an investigational clause):
KRAS covered indications: Suspected or proven metastatic, synchronous or unresectable metachronous colorectal cancer OR undergoing workup for metastasis of non-small cell lung cancer (NSCLC)
Somatic KRAS variant analysis as a stand-alone test in NSCLC is investigational
inv-26: Tumor Specific MGMT Methylation Analysis
Covered when ALL of the following are met for MGMT methylation:
MGMT indications: Member has a high-grade glioma (stage III or IV), including anaplastic oligodendroglioma, anaplastic astrocytoma, anaplastic glioma, or glioblastoma
inv-27: Tumor Specific MLH1 Methylation Analysis
Covered when ALL of the following are met for MLH1 methylation:
MLH1 indications: Diagnosis of colorectal cancer or endometrial (uterine) cancer AND previous tumor testing showed loss of MLH1 on immunohistochemistry (IHC)
MLH1 promoter methylation testing is performed when MLH1 IHC loss is observed
inv-28: Tumor Specific MPL Variant Analysis
Covered when the following clinical picture is present for MPL:
MPL indications: Member displays clinical symptoms of a myeloproliferative neoplasm (e.g., chronically elevated red blood cell counts)
NCCN recommends MPL testing when indicated after JAK2/CALR workup
inv-29: Tumor Specific Microsatellite Instability (MSI) Analysis
Covered when ANY of the following tumor types are present for MSI analysis:
MSI indications: Colorectal OR endometrial OR gastric OR locally advanced/recurrent/metastatic esophageal and esophagogastric junction OR recurrent/progressive/metastatic cervical OR testicular (nonseminoma) after high-dose or third-line therapy OR unresectable/metastatic gallbladder OR unresectable/metastatic intrahepatic or extrahepatic cholangiocarcinoma OR unresectable/metastatic breast OR small bowel adenocarcinoma OR metastatic occult primary
NCCN recommends MSI/MMR testing across these tumor types
inv-30: Tumor Specific NPM1 Variant Analysis
Covered when ALL of the following are met for NPM1:
NPM1 indications: Member has cytogenetically normal acute myeloid leukemia (AML)
inv-31: Tumor Specific NRAS Variant Analysis
Covered when ANY of the following are present for NRAS:
NRAS indications: NRAS variant analysis listed as medically necessary in solid tumors per guideline mappings (detailed diagnoses referenced in source guidance)
See ASCO/CAP/AMP and NCCN mappings for colorectal and other tumor contexts
inv-32: Tumor Specific PIK3CA Variant Analysis
Covered when ANY of the following are present for PIK3CA:
PIK3CA indications: Recurrent or stage IV HR-positive, HER2-negative invasive breast cancer OR diagnosis of uterine rhabdomyosarcoma
inv-33: Tumor Specific RET Variant Analysis
Covered when ANY of the following thyroid or lung cancers are present for RET:
RET indications: Medullary thyroid cancer OR anaplastic thyroid carcinoma or locally recurrent/advanced/metastatic papillary, follicular or Hurthle cell thyroid carcinoma OR advanced or metastatic adenocarcinoma, large cell, or non-small-cell lung cancer
inv-34: Tumor Specific TP53 Variant Analysis
Covered when ANY of the following are present for TP53:
TP53 indications: Diagnosis of AML, CLL or SLL OR undergoing diagnostic workup for mantle cell lymphoma OR suspected or proven metastatic, synchronous or metachronous colorectal cancer
NCCN recommends TP53 testing in lymphoid malignancies for prognosis/treatment selection
Covered when ANY of the following diagnoses are present for MRD analysis:
MRD indications: Acute lymphocytic leukemia (ALL) OR multiple myeloma OR chronic lymphocytic leukemia (CLL)
Codes: 0171U, 0364U; MRD assays should meet sensitivity expectations (ERIC 10^-4) per guideline
inv-36: Tumor Mutational Burden (TMB)
Covered when ANY of the following advanced/metastatic tumor types are present for TMB testing:
TMB indications: Recurrent or metastatic breast cancer OR recurrent/progressive/metastatic cervical cancer OR unresectable/metastatic gallbladder cancer OR unresectable/metastatic extrahepatic cholangiocarcinoma OR suspected metastatic occult primary tumor OR recurrent ovarian/fallopian tube/primary peritoneal cancer OR metastatic or advanced pancreatic adenocarcinoma OR metastatic castration-resistant prostate cancer OR progression of nonseminoma testicular cancer after high-dose or third-line therapy OR endometrial carcinoma or uterine sarcoma
Code: 81479; consider when pembrolizumab or other TMB-informed therapy is being considered per NCCN guidance
inv-37: MRD analysis — medically necessary
Measurable (minimal) residual disease (MRD) analysis is medically necessary when ALL of the following apply:
MRD medical necessity: Member has a diagnosis of Acute Lymphocytic Leukemia (ALL) OR Multiple Myeloma OR Chronic Lymphocytic Leukemia (CLL)
Codes: 0171U, 0364U; use assay sensitivity per ERIC/standardized NGS where applicable (10^-4)
Tumor mutational burden (TMB) testing is medically necessary when the member has any one of the following diagnoses:
TMB indications: Recurrent or metastatic breast cancer; recurrent/progressive/metastatic cervical cancer; unresectable/metastatic gallbladder cancer; unresectable/metastatic extrahepatic cholangiocarcinoma; suspected metastatic malignant occult primary tumor; recurrent ovarian/fallopian tube/primary peritoneal cancer; metastatic or advanced pancreatic adenocarcinoma; metastatic castration-resistant prostate cancer; progression of nonseminoma testicular cancer after high-dose or third-line therapy; endometrial carcinoma or uterine sarcoma.
Code: 81479; consider when TMB-informed therapy (e.g., pembrolizumab) is being considered
inv-39: Red blood cell genotyping — medically necessary
Red blood cell genotyping in multiple myeloma is medically necessary when ALL of the following are met:
RBC genotyping criteria: Member has a diagnosis of multiple myeloma AND member is currently being treated or will be treated with Daratumumab (DARA)
Codes: 0001U, 0180U, 0221U; AABB recommends baseline phenotype and genotype prior to anti-CD38 therapy
inv-40: Cancer exome and genome sequencing — investigational
Cancer exome/genome sequencing stance: Cancer exome and genome sequencing in solid tumors and hematologic malignancies (codes 0036U, 0329U, 81415, 81416, 81425, 81426) is considered investigational.
Investigational — not covered; NCCN does not recommend routine cancer exome/genome sequencing
Specimen identity testing stance: Genetic testing to confirm the identity of laboratory specimens when billed separately (0007U, 0079U, 81265, 81266, 81479) is considered investigational because it is generally part of QA
Investigational — not covered when billed separately
inv-42: Guideline-recommended testing
Covered when testing is recommended by cited guideline for the tumor type or clinical scenario
Guideline-aligned testing: Perform testing as recommended by cited specialty guidelines (examples include: MSI/MMR testing for occult primary and colorectal cancer; broad NGS profiling for advanced/metastatic NSCLC; somatic and germline BRCA1/2 testing in ovarian cancer; JAK2/MPL/CALR testing in suspected MPN; MRD and TMB testing per NCCN/ERIC guidance).
Refer to guideline excerpts for tumor-specific gene/test recommendations
inv-43: Covered per guideline-aligned indications
Covered when aligned with specialty guideline recommendations (examples below):
IGHV and B-cell related testing: IGHV sequencing is recommended by NCCN for CLL/SLL and mantle cell lymphoma and may be useful in certain post-transplant lymphoproliferative disorders or primary cutaneous B-cell lymphoma when adequate biopsy material exists.
MPN panel (JAK2/MPL/CALR): NCCN recommends testing for JAK2 in initial work-up; if negative, test MPL and CALR or use a multigene NGS panel including JAK2, MPL, CALR.
KIT and melanoma/GIST testing: KIT mutation analysis is recommended for GIST and KIT (and BRAF) testing is recommended in stage IV melanoma; broader NGS profiling encouraged for stage IV or recurrent melanoma.
KRAS/NRAS and CRC: All patients with metastatic colorectal cancer should have tumor genotyping for KRAS and NRAS and BRAF mutations because RAS mutations predict lack of response to anti-EGFR therapy.
Inclusion or exclusion of procedure or panel codes in this policy is provided for reference only. Inclusion or exclusion of any codes does not guarantee coverage; providers must reference current professional coding guidance and payer rules prior to claim submission.
This policy does not encompass every type of tumor or genetic test. For tests or scenarios not addressed here—such as certain cytogenetic assays, hereditary cancer susceptibility testing, circulating tumor DNA (liquid biopsy), algorithmic tumor biomarker tests, or whole exome/genome testing—refer to the related Centene policies listed under "Other Related Policies" for specific coverage criteria and guidance.
Many multigene panels and focused tumor tests are designated investigational for indications not meeting the specific criteria
Somatic KRAS variant analysis (codes 81275, 81276) is covered for colorectal cancer and for workup of possible metastasis in NSCLC. However, somatic KRAS testing as a stand-alone test in NSCLC is considered investigational and therefore excluded from coverage in that specific scenario.
Cancer whole exome and genome sequencing (e.g., 0036U, 0329U, 81415–81416, 81425–81426) and separate billing for genetic specimen identity confirmation tests (e.g., 0007U, 0079U, 81265, 81266, 81479) are designated investigational. These services are considered investigational and are excluded from coverage when billed separately.
When somatic tumor testing identifies variants of uncertain significance, clinical decisions should not be based on those findings. Clinical decision making should not be based on a variant of uncertain significance; further evaluation or confirmatory germline testing may be needed if a presumed germline pathogenic variant is suspected.
National Comprehensive Cancer Network (NCCN) guidance does not recommend routine use of whole exome or whole genome sequencing as part of standard cancer evaluation. Therefore, routine cancer exome and genome sequencing is not recommended as a standard diagnostic approach.
NCCN guidelines currently do not support routine cancer exome/genome sequencing or separate genetic testing solely to confirm laboratory specimen identity; these approaches are not recommended as standard practice and are addressed in this policy as investigational when billed separately.
Tumor-type agnostic panels and panels that include IHC or cytogenetic analyses are medically necessary only for the specific clinical scenarios listed (for example, advanced/recurrent/metastatic disease when additional treatment is being sought). For tests and tumor types not explicitly enumerated under the medically necessary criteria, consult this policy and related guidelines—tumor-type agnostic ‘panels’ are investigational for indications not listed.
Tumor-type agnostic (tumor-agnostic) molecular profiling panels are considered investigational for indications other than the specific advanced, recurrent, or metastatic scenarios enumerated in the Coverage Criteria. Tumor-type agnostic panels are investigational for non-enumerated indications.
Covered Indications by Tumor Type and Test
Coding — CPT/HCPCS/ICD Mappings and Examples
Tumor-Type Agnostic Solid Tumor Molecular Profiling - example CPTCPT
Codes referenced are informational; payer may require prior authorization based on current coding and coverage rules. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date professional coding guidance prior to claim submission.
High-level tests requiring coding/prior-authorization awareness: Cancer exome/genome sequencing (0036U, 0329U, 81415, 81416, 81425, 81426) and certain Tumor Mutational Burden (TMB) and MRD tests (e.g., 0364U, 0171U) are listed with CPT/PLA codes and may be subject to prior authorization or considered investigational per coverage rules.
Panel code requirements: If a multigene panel is performed, appropriate panel codes should be used (see hematologic panels 81450, 81451, 81455 and tumor-agnostic panels 81445, 81449, 81455, 81456 and PLA/GSP codes 0037U, 0048U, 0211U, 0244U, 0250U, 0334U).
MRD testing coverage: MRD analysis (0171U, 0364U) in bone marrow or peripheral blood is medically necessary for individuals with ALL, multiple myeloma, or CLL.
Order testing when results will guide therapy: Follow guideline recommendations (NCCN/ASCO) to order molecular testing when results will influence treatment selection for advanced/metastatic tumors (for example, NGS for NSCLC, colorectal cancer genotyping for KRAS/NRAS/BRAF, or MSI/MMR testing for occult primary).
No explicit prior authorization specified in excerpt: While prior authorization may be required by the payer for some tests, no explicit, universal prior authorization requirement is stated in these chunks — verify member-specific PA requirements.
Not Covered / Investigational Tests
This extract does not explicitly label individual tests as universally not covered; where coverage stances are unclear for cytogenetic testing, hereditary genetic testing, ctDNA, algorithmic tests, or whole exome/genome, consult the related Centene policies referenced in the Other Related Policies section for definitive not-covered guidance.
Panels and individual tests described in this policy are marked investigational when used for indications other than those specifically enumerated in the Coverage Criteria sections. Such investigational use is considered not medically necessary and may be denied.
Somatic KRAS variant analysis (81275, 81276) performed as a stand-alone test in a patient with non–small cell lung cancer (NSCLC) is designated investigational and is not covered in that specific clinical scenario.
Routine cancer exome and genome sequencing is not supported by NCCN and is identified in this policy as investigational for routine cancer evaluation; accordingly, routine exome/genome sequencing is not covered as standard evaluation.
Cancer exome/genome sequencing for routine cancer evaluation and genetic testing billed separately to confirm laboratory specimen identity are considered investigational and are not covered when billed as separate services.
DefinitionA presumed germline pathogenic variant (PGPV) is a variant identified on tumor testing that may represent a germline pathogenic variant and could indicate hereditary cancer susceptibility if confirmed in germline testing.
Clinical action
Eligibility Requirements and Preconditions
No explicit family history requirements are stated in the coverage criteria excerpts. Recommendations for genetic counseling and evaluation (for example, after identification of germline or presumed germline variants) are described elsewhere in the policy and in referenced guidelines.
The policy excerpts do not define specific family history thresholds for testing eligibility. When germline pathogenic variants are suspected or identified, follow guideline-recommended genetic counseling and family risk assessment processes described in the related guidance.
No top-level eligibility nodes are specified in this fragment for the listed tests beyond the disease-specific coverage criteria provided under the Coverage Criteria sections.
No top-level eligibility nodes are specified in this fragment for the listed tests beyond the disease-specific coverage criteria provided under the Coverage Criteria sections.
No top-level eligibility nodes are specified in this fragment for the listed tests beyond the disease-specific coverage criteria provided under the Coverage Criteria sections.
No top-level eligibility nodes are specified in this fragment for the listed tests beyond the disease-specific coverage criteria provided under the Coverage Criteria sections.
No top-level eligibility nodes are specified in this fragment for the listed tests beyond the disease-specific coverage criteria provided under the Coverage Criteria sections.
Background and Scope
Molecular analysis of solid tumors and hematologic malignancies identifies somatic oncogenic (driver) mutations that can inform targeted therapy selection, prognosis, and diagnosis. Testing may be performed on tumor tissue or, for hematologic malignancies, on blood or bone marrow. Somatic testing can also reveal presumed germline pathogenic variants, so pre-test counseling and coordination with genetics professionals is recommended when appropriate.
Throughout the Coverage Criteria, each panel type and many tumor-specific tests are explicitly stated as investigational for indications not meeting the listed criteria. Providers should ensure testing is ordered only when it meets the medical necessity conditions described for that panel or test to avoid investigational use.
Revision History
2023-03-01policy_revisionLatest
Policy last revised on 03/01/2023 with updates to medically necessary tumor testing by cancer type and associated coverage criteria.
Policy Summary
PayerCentene
PolicyMolecular Analysis of Solid Tumors and Hematologic Malignancies — Coverage Criteria
Policy CodePolicy N/A
Change TypeNo material change
Effective DateN/A
Next Review DateN/A
Key ActionOrder guideline-recommended molecular testing when results will guide therapy and document counseling for potential incidental germline findings.
Include specified codons/exons per ASCO/CAP/AMP recommendations
MLH1 promoter methylation / BRAF: For colorectal or endometrial tumors with MLH1 IHC loss, test MLH1 promoter methylation (or BRAF V600E) to evaluate for sporadic origin versus Lynch syndrome; absence of BRAF mutation does not exclude Lynch syndrome.
MLH1 methylation testing prerequisite: MLH1 IHC loss
MSI/MMR testing: NCCN recommends determination of MMR/MSI in all colorectal cancer patients and in a range of other tumor types per tumor-specific guidance.
NPM1/AML panel: In AML, test gene mutations including NPM1, c-KIT, FLT3 (ITD/TKD), CEBPA (biallelic), IDH1/2, RUNX1, ASXL1, TP53 and consider multiplex NGS panels for comprehensive prognostic assessment.
TP53 in lymphoid malignancies: TP53 mutation analysis is recommended in mantle cell lymphoma and CLL/SLL to inform prognosis and treatment selection.
MRD testing guidance: MRD testing by flow cytometry and/or molecular methods is recommended in ALL and multiple myeloma for treatment planning and surveillance; for CLL/SLL MRD testing at end of treatment should use assays with sensitivity 10^-4.10^-4
ERIC/standardized NGS sensitivity recommendation
TMB guidance: Consider TMB testing in multiple tumor types when pembrolizumab or other TMB-related therapies are being considered (breast, cervical, hepatobiliary, ovarian, pancreatic, prostate, testicular, uterine).
RBC genotyping guidance: AABB recommends baseline RBC phenotype and genotype prior to initiation of daratumumab; genotyping may be performed after treatment initiation if needed.
Cancer exome/genome sequencing guidance: NCCN does not currently recommend routine cancer exome or genome sequencing as part of evaluation for cancers or tumors.
Investigational / not routinely recommended
Tumor Specific NRASCPTCovered
81311
Tumor specific NRAS variant analysis
Tumor Specific PIK3CAmixedCovered
81309
Tumor specific PIK3CA variant analysis
0155U
PIK3CA - variant testing (proprietary code)
0177U
PIK3CA - variant testing (proprietary code)
Tumor Specific RETCPTCovered
81404
Tumor specific RET variant analysis
81405
Tumor specific RET variant analysis
81406
Tumor specific RET variant analysis
Tumor Specific TP53CPTCovered
81352
Tumor specific TP53 variant analysis
Measurable Residual Disease (MRD)HCPCSCovered
0171U
Measurable (minimal) residual disease analysis
0364U
Measurable (minimal) residual disease analysis
Tumor Mutational Burden (TMB)CPTCovered
81479
Tumor mutational burden (TMB) testing
Medically Necessary MRD TestsCPTCovered
0171U
MRD analysis
0364U
MRD analysis
Medically Necessary TMBCPTCovered
81479
Tumor mutational burden testing
Red Blood Cell Genotyping (Multiple Myeloma + Daratumumab)CPTCovered
0001U
Red blood cell genotyping
0180U
Red blood cell genotyping
0221U
Red blood cell genotyping
Cancer Exome and Genome SequencingCPTNot Covered
0036U
Cancer exome/genome sequencing
0329U
Cancer exome/genome sequencing
81415
Exome/genome sequencing
81416
Exome/genome sequencing
81425
Exome/genome sequencing
81426
Exome/genome sequencing
Genetic testing to confirm specimen identity (investigational when billed separately)mixedNot Covered
0007U
Genetic testing to confirm specimen identity
0079U
Genetic testing to confirm specimen identity
81265
Genetic testing to confirm specimen identity
81266
Genetic testing to confirm specimen identity
81479
Listed here as example billing code
inv-105: MRD / TMB reporting numeric fields
MRD reported numeric fieldsMRD report numeric fields referenced include values 19, 28, 33 mapped in MRD entries (e.g., MyMRD® and ClonoSEQ listings).
MRD CPT/PLA mappingsMRD assays mapped to proprietary CPT/PLA codes: MyMRD® (0171U) and ClonoSEQ (0364U).
TMB reported numeric categoriesTMB numeric category counts referenced include 4, 5, 7, 14, 25, 29–32 as listed in the TMB mapping table.
TMB CPT mappingTMB testing is mapped to CPT 81479 in the coding table.
Associated diagnosis codingTMB and MRD entries reference tumor ICD ranges and specific diagnosis groupings (e.g., C00–D49, C91 and related R codes for MRD).
inv-106: Disease stage requirement
Required disease stageMember must have recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer.
Context for panelsApplies to tumor-type agnostic solid tumor molecular profiling panel tests (listed CPT/PLA codes).
Repeat testing noteRepeat tumor-type agnostic testing is considered medically necessary for specified progressing cancers per the repeat-testing criteria.
inv-107: Prior endocrine therapy requirement for ESR1
Patient eligibility for ESR1 testingPostmenopausal female or adult male with ER-positive, HER2-negative breast cancer.
Prior therapy requirementDisease progression after one or two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor.
CPT mappingESR1 testing is listed with code 81479 in the policy mapping for ESR1 variant analysis.
inv-108: MRD assay sensitivity
Recommended sensitivity for CLL/SLL MRD assaysUse an assay with sensitivity of 10^-4 according to the ERIC standardized method or standardized NGS method.
Context of useRecommendation applies to MRD evaluation at end of treatment for CLL/SLL per NCCN guidance.
Assay modalities referencedMRD assessment may be performed by flow cytometry or molecular/NGS methods; NGS-based assays should meet stated sensitivity.
Investigational indications: Cancer exome/genome sequencing (0036U, 0329U, 81415, 81416, 81425, 81426) is considered investigational. Somatic KRAS testing as a stand-alone in NSCLC is investigational. Genetic specimen identity testing (e.g., know error®, ToxProtect; 0007U, 0079U, 81265, 81266, 81479) when billed separately is investigational.
Investigational tests may be denied: Designated investigational tests billed separately (cancer exome/genome sequencing, specimen identity testing) may be denied as not medically necessary or investigational.
Red blood cell genotyping and serologic testing interference: Baseline RBC phenotype/genotype should be documented for patients with multiple myeloma who will receive daratumumab to mitigate anti-CD38 interference with serologic testing; AABB guidance recommends baseline phenotype/genotype prior to anti-CD38 therapy (may be performed after initiation if needed).
Specimen identity testing documentation mapping: Specimen identity confirmation assays (e.g., know error® DSPA, ToxProtect) map to specific codes (for example, 81265, 81266, 81479) but are generally considered investigational when billed separately; follow billing guidance and do not duplicate charges.
Documentation / assay expectations: For MRD testing in CLL/SLL use an assay sensitivity of 10^-4 per ERIC standardized or standardized NGS method and document the assay used. Document clinical justification for RBC genotyping when anti-CD38 monoclonal antibody is planned or administered.
ESR1 step therapy requirement: Tumor-specific ESR1 variant analysis (81479) is medically necessary only for ER-positive, HER2-negative breast cancer after disease progression following one or two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor.
Step therapy: For tests with step or sequencing requirements (for example ESR1), ensure prior lines of therapy are documented per clinical criteria before ordering/testing.
Not applicable/Other guidance: This COA is not intended to address liquid biopsies; tumor-normal paired strategies and documentation of potential incidental germline findings should be communicated to patients prior to testing.
Billing Rule
Panel Code Requirements & Clinical Criteria
Tumor-type agnostic solid tumor molecular profiling panels and tumor-type agnostic panels with IHC/cytogenetics have defined medical necessity criteria and repeat-testing rules. Use appropriate panel codes when ordering multigene panels. Panels with IHC/cytogenetic analyses are medically necessary for advanced/recurrent/metastatic disease when the member is seeking further cancer treatment; repeat testing is limited to specified progressing tumor types. Comprehensive hematologic panels have specific indications and are investigational for other uses.
Use appropriate panel codes for multigene panels (note: 81445, 81449, 81455, 81456, 0211U, 0037U, 0048U, 0244U, 0250U, 0334U as applicable).
Tumor-type agnostic panels with IHC/cytogenetics (0211U, 81455, 0379U) are medically necessary for recurrent/relapsed/refractory/metastatic or advanced (stage III/IV) cancer when further cancer-directed therapy is being sought; repeat testing criteria apply and investigational for other indications.
Comprehensive molecular profiling panels for hematologic malignancies (81450, 81451, 81455) are medically necessary for defined AML, MDS, suspected myeloproliferative neoplasm, or specific CML progression scenarios; investigational for other indications.
Documentation Required
MRD Testing Coverage & Documentation
MRD analysis is covered for hematologic malignancies when specific diagnoses are present. Document the diagnosis and the assay used; ensure assay sensitivity meets guideline expectations for the disease.
Covered MRD CPT/PLA codes include 0171U and 0364U for bone marrow or peripheral blood when the member has ALL, multiple myeloma, or CLL.
For CLL/SLL MRD testing, use an assay with sensitivity of 10^-4 per ERIC standardized method or standardized NGS method and document the method used.
Note
Order Testing When Results Will Guide Therapy
Order molecular testing when results will guide therapy selection. Follow NCCN/ASCO guideline recommendations for molecular testing in specific tumor types to identify actionable genomic aberrations that impact treatment.
Examples: Broad NGS for advanced/metastatic NSCLC to detect EGFR/ALK/ROS1/BRAF/NTRK/MET/RET and others; tumor genotyping in metastatic colorectal cancer for KRAS/NRAS/BRAF; MSI/MMR testing per occult primary guidelines; BRCA germline and somatic testing in ovarian cancer.
Document how test results will influence therapeutic decisions in the medical record.
Denial Risk
Investigational Indications & Denial Risk
Investigational tests and certain indications are not covered and may be denied. Providers should avoid billing investigational assays separately when they are considered part of internal laboratory QA or investigational services.
Cancer exome/genome sequencing (0036U, 0329U, 81415, 81416, 81425, 81426) is considered investigational.
Genetic testing to confirm specimen identity (e.g., know error®, ToxProtect; 0007U, 0079U, 81265, 81266, 81479) when billed separately is considered investigational and may be denied.
Somatic KRAS analysis as a stand-alone test in NSCLC (81275, 81276) is investigational.
PGPV findings on somatic testing should prompt documentation of pre-test counseling and consideration of confirmatory germline testing and genetic evaluation.
Counseling recommendationProviders should inform patients that somatic tumor testing may reveal incidental germline findings and document pre-test counseling and discussion of PGPVs.
DefinitionMeasurable (Minimal) Residual Disease (MRD) analysis refers to assays used to detect minimal residual disease using NGS or other sensitive methods (examples include MyMRD® NGS Panel and ClonoSEQ).
Clinical indicationsMRD analysis in bone marrow or peripheral blood is medically necessary for ALL, multiple myeloma, and CLL per the policy.
Coding examplesMRD assays are mapped to codes such as 0171U (MyMRD®) and 0364U (ClonoSEQ) in the policy's coding table.
DefinitionTumor Mutational Burden (TMB) and Microsatellite Instability (MSI) are genomic measures characterizing tumor mutational load or genomic instability; MSI testing maps to CPT 81301 and TMB is commonly billed to CPT 81479 in the policy mappings.
Clinical relevanceTMB is under study as a predictive biomarker for immunotherapy response; MSI/MMR testing is used across multiple tumor types to inform therapy and hereditary cancer risk evaluation.
Coding notePolicy maps MSI to 81301 and TMB to 81479 where applicable in the coding tables and indication sections.
inv-146: Comprehensive molecular profiling panels for hematologic malignancies
DefinitionComprehensive molecular profiling panels for hematologic malignancies are multigene panels performed on bone marrow or peripheral blood for evaluation of AML, MDS with persistent cytopenias, suspected MPN, or CML progression.
Panel codesRepresentative CPT codes include 81450, 81451, and 81455 for comprehensive hematologic panels as listed in the policy.
Ordering contextComprehensive panels may be ordered as initial evaluation or after targeted JAK2/CALR/MPL testing when appropriate and indicated.
inv-147: MRD analysis
DefinitionMRD analysis is measurable (minimal) residual disease analysis in bone marrow or peripheral blood used to assess residual disease in ALL, multiple myeloma, and CLL.
Assay examplesExamples include NGS-based tests such as MyMRD® and ClonoSEQ and flow cytometry approaches referenced in guideline discussion.
Clinical useMRD results guide consolidation, surveillance, and treatment planning per NCCN recommendations in ALL and multiple myeloma, and at end of treatment in CLL/SLL.
inv-148: MSI analysis
DefinitionMSI analysis is tumor microsatellite instability testing used for specified solid tumors (e.g., colorectal, endometrial, gastric, and select metastatic cancers).
MethodsMSI can be performed by PCR or NGS; MMR protein status is assessed by immunohistochemistry (IHC) as referenced in guideline-aligned sections.
Coding mappingMSI testing is mapped to CPT 81301 in the policy coding table where applicable.
inv-149: Tumor mutation burden (TMB)
DefinitionTumor mutation burden (TMB) is a measure of the number of mutations carried by tumor cells and is evaluated as a potential predictive biomarker for immunotherapy response.
CodingPolicy maps TMB testing to CPT 81479 in coding tables and indicates tumor-type specific indications for use.
Clinical useTMB testing is considered medically necessary for listed recurrent/metastatic tumor types when TMB-informed therapy is being considered.
inv-150: Advanced cancer definition
DefinitionComprehensive molecular profiling panels for hematologic malignancies are multigene panels performed on bone marrow or peripheral blood to evaluate AML, MDS, suspected MPN, or CML progression.
Use casesPanels are covered when blood work and bone marrow evaluation are consistent with AML, newly diagnosed MDS with persistent cytopenias, suspected MPN, or CML with progression.
Coding guidanceIf a multigene panel is performed, appropriate panel codes (e.g., 81450, 81451, 81455) should be used per the policy note.
inv-151: Somatic (tumor) testing definition
DefinitionSomatic (tumor) testing is genomic testing performed on tumor tissue to identify actionable genomic aberrations and guide targeted or tumor-agnostic therapies.
Potential findingsSomatic testing can identify driver mutations and may reveal presumed germline pathogenic variants requiring further germline evaluation.
Testing strategiesApproaches include tumor-only testing and tumor-normal paired testing with germline subtraction or explicit germline analysis.
inv-152: Germline testing definition
DefinitionGermline testing is genetic testing of blood or normal tissue to identify inherited pathogenic variants (e.g., BRCA1/2) relevant for treatment decisions and familial risk.
Relation to somatic testingWhen tumor testing suggests a presumed germline pathogenic variant, confirmatory germline testing is recommended and genetic counseling should be provided.
Guideline recommendationASCO recommends germline testing for all women with epithelial ovarian cancer and coordination with providers familiar with hereditary cancer management.
inv-153: MRD recommended sensitivity
Recommended MRD sensitivity for CLL/SLLFor CLL/SLL use an assay with sensitivity of 10^-4 per ERIC standardized or standardized NGS method.
Guideline sourceRecommendation cited from NCCN guidance for CLL/SLL in the policy notes and definitions.
ApplicationThis sensitivity expectation applies to MRD testing performed at the end of treatment for CLL/SLL as part of surveillance or treatment decisions.
inv-154: MSI / MMR
DefinitionMSI/MMR testing includes tumor testing using PCR or NGS for MSI and immunohistochemistry (IHC) for mismatch repair (MMR) proteins across multiple tumor types.
Clinical roleMSI/MMR testing is used for diagnostic, prognostic, and hereditary cancer risk assessment and informs therapy such as immune checkpoint inhibitors.
Coding mappingMSI testing is mapped to CPT 81301 in the policy coding tables and associated with multiple tumor-specific indications.
inv-155: Anti-CD38 interference with serologic testing
DefinitionAnti-CD38 interference with serologic testing describes how anti-CD38 monoclonal antibodies (e.g., daratumumab) can interfere with red blood cell serologic testing and transfusion compatibility testing.
Clinical recommendationAABB recommends baseline RBC phenotype and genotype prior to initiation of daratumumab to mitigate serologic testing interference; genotyping may be performed after treatment initiation if needed.
Coverage implicationPolicy states RBC genotyping is medically necessary for multiple myeloma patients being treated with or planned for daratumumab (codes: 0001U, 0180U, 0221U).