CurrentCentenePolicy N/A

Concert Genetic Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies (PDF)

Defines the clinical context, examples of tests/labs, and coding implications for molecular profiling panels, targeted/single-gene tests, fusion panels, MRD assays, TMB/MSI, transplantation HLA testing, and exome/genome sequencing for solid tumors and hematologic malignancies.

Policy Summary

PayerCentene

PolicyConcert Genetic Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies (PDF)

Policy CodePolicy N/A

Change TypeCoding and criteria updates; new MRD and RNA fusion criteria

Effective Date

Next Review Date

Key ActionProviders should communicate the potential for incidental clinically relevant germline findings to patients prior to somatic mutation profiling.

SourceLink

POLICY UPDATE CHANGES

Added CPT code 0422U for Solid Tumor MRD Testing.

Added CPT codes 81457, 81458, 81459 to Tumor-Type Agnostic Solid Tumor Molecular Profiling criteria.

Replaced multiple prior codes (e.g., 81449 replaced with 81455; 0211U replaced with 0379U; 0329U replaced with 0297U).

Added Targeted and Broad RNA Fusion Panel Tests and coverage for Broad RNA Fusion Panels in acute lymphoblastic leukemia.

Expanded and clarified tumor-type specific coverage criteria (TMB, MSI, numerous gene-specific variant analyses) to align with updated NCCN guideline versions.

Removed Tumor Specific RET Variant Analysis content and other listed codes/content (e.g., 0079U).

Reworded and clarified multiple criteria (e.g., MPN panel gene list changed to minimum JAK2, CALR, MPL).

HPV-Related Solid Tumor MRD Testing: NEW Criteria for coverage based on LCD; investigational criterion removed.

Evidence-Based Solid Tumor MRD Testing: NEW Criteria set created based on LCD with updated covered tumor types for Signatera.

Emerging Evidence Solid Tumor MRD Testing: NEW investigational criteria for MRD tests without established clinical validity.

Tumor Mutational Burden (TMB) criteria expanded to cover any recurrent/refractory/metastatic or advanced stage III/IV cancer (excluding CNS) with progression on prior treatment and no satisfactory options.

Tumor Specific BRAF Variant Analysis: coverage expanded to include certain esophageal and gastric cancers per NCCN.

Tumor Specific CEBPA Variant Analysis: expanded coverage to all patients evaluated for AML.

Red Blood Cell Genotyping in Multiple Myeloma: coverage expanded to patients considered for Isatuximab.

Tumor Specific BCR/ABL1 Kinase Domain Analysis: clarified that Ph-positive ALL is a covered indication.

Multiple updates: NCCN guideline version date updates across many tumor-specific criteria and Background/Rationale and References.

HLA Typing for Transplantation: NEW criteria set created; investigational criterion removed.

>=1CPT codes added in this part

MixedCoverage stance across tests

11/2024Date of Last Revision (documented)

extensiveCPT/HCPCS codes referenced

NEW MRD criteriaNew coverage categories added

Coverage Summary

Somatic genomic profiling of tumors is used for diagnosis, prognosis, and treatment selection by identifying somatic oncogenic “driver” mutations, and also for identifying TMB, MSI, gene fusions, and for monitoring measurable (MRD) in solid tumors and hematologic malignancies. Tumor testing strategies are evolving and include tumor-only testing, tumor-normal paired testing with germline subtraction, and tumor-normal paired testing with explicit analysis of genes associated with germline predisposition; incidental germline findings can occur and providers should communicate this possibility to patients before testing.

Exome and whole-genome tumor sequencing are recognized as an active area of research and are not routinely recommended by guidelines for standard evaluation at this time.

Coverage stance across the policy is mixed: many tumor-type agnostic panels, targeted fusion and tumor-specific single-gene tests, hematologic panels, select MRD cell-free DNA assays, TMB and MSI testing, HLA typing for transplantation, and red blood cell genotyping in multiple myeloma have defined medically necessary indications when criteria are met, while cancer exome/genome sequencing and certain specimen-identity testing when billed separately are considered investigational.

Scope summary: defines clinical context, example tests and CPT/HCPCS codes, and criteria for tumor-type agnostic panels, targeted and broad RNA fusion panels, tumor-specific single-gene/variant analyses, hematologic/myeloid panels, MRD assays (evidence-based and emerging), TMB/MSI testing, HLA typing for transplant, and cancer exome/genome sequencing; includes coding implications and alignment to NCCN, ASCO and CMS (MolDX) guidance.

Key thresholds and operational summary

RNA fusion panel (targeted)5-50 genes

Broad RNA fusion panel51+ genes

MRD testing frequency (Concert default)Once per cancer diagnosis (patients with cancer); once every 12 months (patients without cancer)

Cytopenia duration for MDS testing4-6 months

TMB-H threshold>=10 mut/Mb

Policy last_review11/2024

Policy versionV1.2025

Medical-Necessity Criteria

Overview / Clinical Context

Overview / Clinical Context: The molecular analysis of solid tumors and hematologic malignancies aims to identify somatic oncogenic mutations for diagnosis, prognosis, treatment selection, and monitoring. Testing strategies include tumor-only testing, tumor-normal paired testing with germline subtraction, and paired testing with explicit germline gene analysis. Providers should inform patients about possible incidental germline findings. Clinical decision-making should not be based on variants of uncertain significance (VUS).

Purpose: Identify somatic driver mutations to inform targeted therapy, prognosis, and diagnostic classification for solid tumors and hematologic malignancies.

Testing strategies: tumor-only testing; tumor-normal paired testing with germline variant subtraction; tumor-normal paired testing with explicit analysis of genes associated with germline cancer predisposition.

Incidental germline findings: Molecular tumor testing may uncover variants suggestive of germline pathogenicity. Providers must communicate the potential for incidental germline findings prior to testing and manage confirmatory germline testing and counseling per standard clinical practice.

Coding

Tumor-Type Agnostic Solid Tumor Molecular Profiling Panels - example tests and common CPT/HCPCSmixed

0037U	FoundationOne CDx (example)
0048U	MSK-IMPACT (example)
0329U	Oncomap ExTra (example)
81445	NGS multigene; used by several tumor-type agnostic panels
81455	Sequencing; used by several panels
81457	NGS multigene; used by several panels
81458	NGS multigene; used by several panels
0334U	Guardant360 TissueNext (example)
0250U	PGDx elio tissue complete (example)
81459	OmniSeq INSIGHT / Tempus xT w/ PD-L1 IHC (example)

1–10 of 12

1/2

Targeted RNA Fusion Panelsmixed

81449	Targeted Solid Tumor NGS Fusion Panel (NeoGenomics) - example mapping
81456	Broad RNA fusion panel (Tempus xR) - example
0444U	Aventa FusionPlus (example)

Broad RNA Fusion Panels (covered for ALL)mixedCovered

0444U	Aventa FusionPlus (example)
81456	Tempus xR Whole Transcriptome RNA Sequencing (example)

Broad molecular profiling panels for hematologic/myeloid malignanciesmixed

81450	FoundationOne Heme / broad hematologic panels (example)
81455	Sequencing component used by hematologic panels (example)

Tumor-specific single gene / variant analysesmixed

81170	BCR/ABL1 kinase domain mutation analysis
81210	BRAF variant analysis
81162	BRCA1/2 variant analysis (NGS tumor)
81219	CALR variant analysis
81218	CEBPA variant analysis
81235	EGFR variant analysis
81245	FLT3 ITD/TKD mutation analysis (PCR)
81120	IDH1 variant analysis
81121	IDH2 variant analysis
81261	IGHV/IgVH mutation analysis

1–10 of 17

1/2

MRD / Minimal Residual Disease Testingmixed

0171U	MyMRD NGS Panel Assay (hematologic MRD)
0364U	ClonoSEQ Assay (hematologic MRD)
0340U	Signatera (evidence-based solid tumor MRD)
81479	Guardant Reveal - MRD (example)
0422U	Guardant360 Response (example)

Emerging / Evidence-status MRD testsHCPCS

0229U	COLVERA (example emerging)
0306U	Invitae Personalized Cancer Monitoring - Baseline (example)
0307U	Invitae Personalized Cancer Monitoring - Monitoring (example)
0486U	Northstar Response (example)
0498U	OptiSeq Colorectal Cancer NGS Panel (example)
0501U	QuantiDNA Colorectal Cancer Triage Test (example)
0356U	NavDx (HPV-related MRD) (example)

Cancer Exome / Genome Sequencingmixed

0221U	Cancer exome/genome sequencing (example mapping)
0297U	Somatic whole genome sequencing (Praxis Genomics) example
81415	Exome/genome sequencing components
81416	Exome/genome sequencing components
81425	Genome sequencing components
81426	Genome sequencing components
0036U	EXaCT-1 Whole Exome Testing (Weill Cornell) example

HLA Typing for Transplantationmixed

81370	HLA typing (intermediate resolution) example
81371	HLA typing example
81372	HLA typing example
81373	HLA typing example
81376	HLA-DQB1,DQA1 intermediate resolution (example)
81378	HLA high resolution / panel by NGS (example)
81379	HLA A,B,C profile high resolution (example)
81380	HLA A high resolution (example)
81382	HLA high resolution panel (example)

Tumor-type agnostic panel / broad somatic profiling codes (medically necessary per criteria)mixedCovered

0037U	PLA / panel
0048U	PLA / panel
0250U	PLA / panel
0329U	PLA / panel
0334U	PLA / panel
0379U	PLA / panel
0391U	PLA / panel
81445	Somatic tumor panel
81455	Comprehensive genomic profiling
81457	Tumor panel

1–10 of 12

1/2

Targeted RNA fusion panels (medically necessary per criteria)mixedCovered

81449

RNA fusion panel (5-50 genes)

Broad RNA fusion panels (medically necessary for ALL)mixedCovered

0444U	RNA fusion panel (51+ genes)
81456	Broad RNA fusion panel

Cancer exome/genome sequencing (investigational)mixedExperimental

0036U	Cancer exome/genome sequencing
0297U	Cancer exome/genome sequencing
81415	Exome sequencing
81416	Exome sequencing
81425	Genome sequencing
81426	Genome sequencing

Tumor-specific single-gene/variant and other assays (medically necessary per criteria)mixedCovered

81170	BCR-ABL1 kinase domain analysis
0016U	BCR-ABL1 FISH / qualitative
0040U	BCR-ABL1 test
81479	Multiple uses (e.g., ESR1, other assays)
88271	Cytogenetic analysis
81210	BRAF variant analysis
81162	BRCA1/2 variant analysis
81218	CEBPA variant analysis
81235	EGFR variant analysis
81245	FLT3 variant analysis

1–10 of 25

1/3

Genetic testing to confirm specimen identity (investigational when billed separately)mixedExperimental

81265	Specimen identity testing
81266	Specimen identity testing
81479	Used for some confirmatory assays

Hematologic MRD tests (medically necessary)mixedCovered

0171U	MyMRD NGS Panel Assay (hematologic MRD)
0364U	ClonoSEQ Assay (hematologic MRD)

Tumor-Type ICD-10 groups referencedICD-10

C00-D49	Neoplasms (used widely across tumor-agnostic tests)
Z85	Personal history of malignant neoplasm
C34	Malignant neoplasm of bronchus and lung
C91	Lymphoid leukemia group
C92	Myeloid leukemia group
D46.9	Myelodysplastic syndrome unspecified
C43	Melanoma (cutaneous melanoma panels)
D03	Melanoma in situ (melanoma panels)
C56	Ovarian cancer (BRCA tumor testing context)
C61	Prostate cancer (BRCA tumor testing context)

Provider Actions

Documentation Required

Pre-test counseling regarding incidental germline findings

Prior to somatic tumor profiling, providers should counsel patients about the potential to identify incidental presumed germline pathogenic variants (PGPVs) and other clinically relevant germline findings. Document that pre-test counseling occurred and that the patient was informed about the possibility of germline results and subsequent confirmatory germline testing if indicated.

Prior Authorization

Use appropriate panel codes and ensure indication meets criteria

Order panels using appropriate, up-to-date CPT/HCPCS panel codes and ensure the clinical indication matches the policy criteria and current guideline-directed indications (NCCN, FDA) or applicable Local Coverage Determinations (LCDs). See code_groups for applicable codes and verify that the selected code reflects the test methodology and intended clinical use.

See code_groups for applicable codes

Background and Evidence

Somatic molecular profiling evaluates tumors (tissue, blood/ctDNA, or bone marrow/peripheral blood for hematologic malignancies) to identify somatic driver mutations to inform targeted therapy selection, prognostication, and diagnosis. It also detects biomarkers such as TMB, MSI, and gene fusions, which can predict response to therapies (for example, immunotherapy) and be useful across tumor types.

Testing approaches include tumor-only sequencing, and tumor-normal paired strategies either for germline subtraction or with explicit germline predisposition gene analysis; this is an evolving area and providers should counsel patients about the potential for incidental germline findings prior to somatic testing.

Analysis of complete tumor DNA via whole-exome or whole-genome sequencing is acknowledged as an area of ongoing research and is considered investigational by the policy when used routinely, with exome/genome sequencing listed as investigational in coverage sections.

Molecular assays can also be applied to monitor measurable (minimal) residual disease (MRD) in hematologic and solid tumors; MRD coverage is separated into evidence-based (cell-free DNA assays with demonstrated clinical validity per CMS MolDX criteria) and emerging investigational MRD tests that lack established clinical validity. The CMS/MolDX LCD criteria for MRD emphasize (1) patient personal history of cancer within test intended use, (2) that detection of recurrence/progression would change management, and (3) tests must demonstrate ability to identify molecular recurrence/progression before clinical/radiographic evidence with adequate sensitivity/specificity.

Coding and operational implications are provided: example and commonly used CPT/HCPCS PLA codes for tumor-agnostic panels, targeted and broad fusion panels, hematologic panels, MRD assays, exome/genome sequencing codes, and specimen identity codes are listed as examples and do not guarantee coverage; providers should reference current CPT guidance and the Concert Platform for registered tests.

Medicare / LCD Determinations

Determination	Type/Number	Notes
MolDX: Minimal Residual Disease Testing for Cancer (LCD)
L38779
CMS MolDX LCD outlining MRD coverage criteria: personal history within intended use, recurrence/progression that would change management, and evidence test detects molecular recurrence before clinical/radiographic evidence with adequate sensitivity/specificity (referenced in policy).
MolDX: Billing and Coding: Minimal Residual Disease Testing for Solid Tumor Cancers (Article)
A58376
CMS billing/coding article clarifies intended uses meeting clinical validity (eg diagnosis of recurrence/progression for select cancers, monitoring response to immune checkpoint inhibitor therapy) and test-specific frequency guidance referenced in policy.

Revision History

11/2024latest_reviewLatest

Last review 11/2024 (document V1.2025).

retired/redeveloped

MRD testing criteria retired and redeveloped into two criteria sets based on LCD guidelines.

added (coding)

Added CPT code 0422U for Solid Tumor MRD Testing.

Policy Summary

PayerCentene

PolicyConcert Genetic Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies (PDF)

Policy CodePolicy N/A

Change TypeCoding and criteria updates; new MRD and RNA fusion criteria

Effective Date

Next Review Date

Key ActionProviders should communicate the potential for incidental clinically relevant germline findings to patients prior to somatic mutation profiling.

SourceLink

On This Page

Variants of Uncertain Significance (VUS): Clinical decisions should not be based on VUS; VUS should be reported per laboratory policy but not used for therapy selection.

Tumor-Type Agnostic Solid Tumor Molecular Profiling Panels - Medically Necessary

Tumor-Type Agnostic Solid Tumor Molecular Profiling Panels — Medically Necessary when the following are met. Named example panel codes in introductory material include: 0037U, 0048U, 0329U, 0334U, 0250U, 0379U, 0391U, 81445, 81455, 81457, 81458, 81459, 81458, 81456, 0444U.

ALL of the following

Diagnosis of a malignant solid tumor (new or recurrent) where results may impact systemic therapy selection, clinical trial eligibility, or prognostic assessment.
Testing is ordered by an oncologist or appropriate specialist knowledgeable in interpretation of results and implications for management.
There is sufficient and appropriate tumor tissue available or a validated alternative (e.g., validated ctDNA assay when tissue unobtainable).
Results will be used to guide treatment selection, to determine eligibility for approved targeted therapy, or enrollment in clinical trials.

ONE of

Advanced, metastatic, or recurrent solid tumor for which standard therapies have failed or are limited and broad molecular profiling may identify actionable alterations.
New diagnosis of certain tumor types for which comprehensive genomic profiling is guideline-recommended to determine first-line targeted therapy (e.g., specific NSCLC, cholangiocarcinoma, or other guideline-specified cancers).
Tumor histology where multiple biomarker targets across many genes influence therapy selection and single-gene testing is inadequate.

Tumor-Type Agnostic Solid Tumor Molecular Profiling Panels - Alternate Indications

Tumor-Type Agnostic Solid Tumor Molecular Profiling Panels — Alternate Indications (medically reasonable but context-dependent).

ANY of the following

When tissue is insufficient for standard single-gene assays and broad panel may maximize information from limited sample.
For identification of biomarkers to determine eligibility for FDA-approved companion diagnostics or targeted therapies when single-analyte test not available or practical.

Tumor-Type Agnostic Solid Tumor Molecular Profiling Panels - Repeat Testing

Tumor-Type Agnostic Solid Tumor Molecular Profiling Panels — Repeat Testing.

ANY of the following

Repeat broad molecular profiling is medically necessary when there is disease progression or change in histology suggesting new actionable alterations that would alter management and prior testing was performed on earlier specimen not reflective of current disease state.
Repeat testing is not indicated solely for monitoring when validated MRD or targeted assays are available and more appropriate.

Tumor-Type Agnostic Solid Tumor Molecular Profiling Panels - Investigational

Tumor-Type Agnostic Solid Tumor Molecular Profiling Panels — Investigational when used outside established indications or when the panel includes unvalidated analytes.

ALL of the following

Panels that include unvalidated biomarkers without demonstrated clinical utility or that are used for screening asymptomatic individuals.
Panels performed for broad genomic discovery in absence of intent to use results for clinical management or clinical trial enrollment.

Targeted RNA Fusion Panels (81449) - Medically Necessary

Targeted RNA Fusion Panels (CPT 81449) — Medically Necessary when the following apply.

ALL of the following

Patient has a tumor type in which specific gene fusions are established oncogenic drivers and influence therapy selection (e.g., NTRK, ALK, ROS1, RET in specified cancers).
Testing is ordered to detect clinically actionable fusions not adequately covered by DNA-based panels or IHC and will influence treatment.

Targeted RNA Fusion Panels (81449) - Investigational

Targeted RNA Fusion Panels (81449) — Investigational when used for broad, untargeted discovery of fusions without clear clinical actionability.

ALL of the following

Use for fusion discovery in tumor types where clinical utility of identified fusions is unproven.

Broad RNA Fusion Panels (0444U, 81456) - Medically Necessary

Broad RNA Fusion Panels (0444U, 81456) — Medically Necessary when fusion detection will guide FDA-approved therapy or trial enrollment and when DNA-based testing is insufficient.

ALL of the following

Patient has tumor type with potential actionable fusions across many genes and detection would change management.
Specimen quality and assay validation are adequate for reliable fusion detection.

Broad RNA Fusion Panels - Investigational

Broad RNA Fusion Panels — Investigational for general screening or in tumor types without established fusion-directed therapies.

ALL of the following

Used for exploratory fusion discovery without expectation of immediate clinical utility.

Broad Molecular Profiling Panels for Hematologic/Myeloid Malignancies - Medically Necessary

Broad Molecular Profiling Panels for Hematologic/Myeloid Malignancies — Medically Necessary when criteria below are met. This includes myeloid-focused panels used to establish diagnosis, prognostic classification, inform therapy selection (including targeted agents), or allogeneic transplant planning.

ALL of the following

Suspected or confirmed hematologic malignancy (e.g., AML, MDS, MPN) where multi-gene myeloid panel informs diagnosis, prognostic risk stratification, or therapy selection.
Testing performed on appropriate specimen (bone marrow or peripheral blood with adequate tumor fraction) and ordered by treating hematologist/oncologist or transfusion/transplant specialist.
Panel includes genes with established clinical relevance for the specific hematologic disorder (e.g., NPM1, FLT3, CEBPA, TP53, RUNX1, ASXL1, IDH1/2, JAK2, CALR, MPL among others) and the laboratory reports variant allele fractions and clinically relevant annotations.
Results will be used to guide induction/targeted therapy, transplant decisions, prognostic classification, or enrollment in genotype-selected clinical trials.

Examples of medically necessary myeloid-focused panel uses

Newly diagnosed AML: broad myeloid panel to identify targetable mutations (IDH1/2, FLT3) and provide prognostic information (NPM1, CEBPA, TP53).
MDS/MPN overlap or unclear morphology where molecular testing refines diagnosis and risk stratification.
Pre-transplant assessment when molecular profile influences donor selection, conditioning, or post-transplant monitoring.

Broad Molecular Profiling Panels for Hematologic/Myeloid Malignancies - Repeat Testing

Broad Molecular Profiling Panels for Hematologic/Myeloid Malignancies — Repeat Testing: when clinically indicated.

ANY of the following

Repeat broad panel testing is medically necessary at disease progression or relapse if new actionable mutations are suspected and prior testing does not reflect current disease biology (e.g., post-therapy clonal evolution).
Repeat testing is indicated when prior testing was performed on inadequate specimen or prior to disease-modifying therapy expected to induce clonal selection.

Broad Molecular Profiling Panels for Hematologic/Myeloid Malignancies - Investigational

Broad Molecular Profiling Panels for Hematologic/Myeloid Malignancies — Investigational when panels include unvalidated genes or are used for broad discovery without actionability.

ALL of the following

Panels used solely for research or discovery without established clinical utility for management decisions.

Colorectal Cancer Focused Molecular Profiling Panels - Medically Necessary

Colorectal Cancer Focused Molecular Profiling Panels — Medically Necessary when results guide therapy selection (e.g., RAS/RAF status, MSI, TMB where applicable).

ALL of the following

Diagnosed colorectal cancer where biomarkers will determine eligibility for targeted therapies or immunotherapy (e.g., RAS, BRAF V600E, MSI/MMR).

Colorectal Panels - Investigational

Colorectal Panels — Investigational when used to assess unproven biomarkers or for screening asymptomatic individuals.

ALL of the following

Use for exploratory purposes without expectation of changing clinical management.

Lung Cancer Focused Molecular Profiling Panels - Medically Necessary

Lung Cancer Focused Molecular Profiling Panels — Medically Necessary when testing for guideline-recommended biomarkers (e.g., EGFR, ALK, ROS1, BRAF, NTRK, MET, RET, KRAS) to guide first-line or subsequent therapy.

ALL of the following

Patients with advanced NSCLC where results will determine eligibility for approved targeted therapies or trials.

Lung Panels - Repeat Testing

Lung Panels — Repeat Testing may be appropriate at progression when resistance mutations are suspected (e.g., EGFR T790M, MET amplification).

ANY of the following

Repeat testing at acquired resistance to guide subsequent targeted therapy when prior specimen predates targeted treatment or resistance mechanisms are suspected.

Lung Panels - Investigational

Lung Panels — Investigational when assessing unvalidated markers without clinical actionability.

ALL of the following

Panels used for research or discovery without immediate clinical application.

Cutaneous Melanoma Focused Panels - Medically Necessary

Cutaneous Melanoma Focused Panels — Medically Necessary when testing for actionable mutations (e.g., BRAF) that guide therapy selection.

ALL of the following

Advanced or metastatic melanoma where identification of BRAF V600 and other actionable mutations will impact targeted therapy choice.

Cutaneous Melanoma Panels - Investigational

Cutaneous Melanoma Panels — Investigational when used to assess markers without established therapy implications.

ALL of the following

Exploratory testing without intent to change management.

Acute Myeloid Leukemia (AML) Focused Panels - Medically Necessary

Acute Myeloid Leukemia (AML) Focused Panels — Medically Necessary when used to identify diagnostic and prognostic mutations and to guide targeted therapy.

ALL of the following

Newly diagnosed AML: perform myeloid molecular panel to detect mutations with therapeutic or prognostic significance (e.g., NPM1, FLT3-ITD/TKD, IDH1/2, TP53, RUNX1).
Testing ordered prior to initiation of definitive therapy when results will impact induction or targeted treatment choices or transplant planning.

Acute Myeloid Leukemia Panels - Investigational

Acute Myeloid Leukemia Panels — Investigational when panels include genes without demonstrated clinical utility in AML management.

ALL of the following

Panels performed for broad discovery without immediate clinical applicability.

Myeloproliferative Neoplasm (MPN) Panels

Myeloproliferative Neoplasm (MPN) Panels — Medically Necessary when testing for JAK2, CALR, MPL and other genes to establish diagnosis and guide management.

ALL of the following

Patients with clinical suspicion of MPN where molecular testing supports diagnostic confirmation (JAK2, CALR, MPL) or informs therapy.

Tumor Specific BCR/ABL1 Kinase Domain Analysis (81170)

Tumor-Specific BCR/ABL1 Kinase Domain Analysis (81170) — Medically Necessary when monitoring for resistance mutations in patients with BCR-ABL1-positive leukemias on tyrosine kinase inhibitor therapy.

ALL of the following

Patient with BCR-ABL1-positive chronic myeloid leukemia or Ph+ ALL receiving TKI therapy with suboptimal response or loss of response; testing for kinase domain mutations will inform change of therapy.

Tumor Specific BCR/ABL1 FISH/Qualitative/Quantitative Tests

Tumor-Specific BCR/ABL1 FISH/Qualitative/Quantitative Tests — Use per disease-specific monitoring guidelines; panels and methods vary by clinical context.

ANY of the following

Cytogenetic, FISH, and quantitative PCR methods are used appropriately for diagnosis and MRD monitoring per hematologic malignancy guidelines and clinician judgment.

Tumor Specific Variant Analyses — gene-specific examples

Tumor Specific Variant Analyses — gene-specific examples of medically necessary single-gene or small panel testing when results will directly guide therapy or prognosis.

EGFR: single-gene or focused testing when altering therapy selection in NSCLC (exons and alterations per guideline).

ALK/ROS1/RET/NTRK: focused testing in tumor types where fusions confer eligibility for targeted agents.

KRAS: testing in colorectal and other cancers to guide anti-EGFR therapy decisions.

BRAF: testing in melanoma and colorectal cancer to identify V600 and other actionable variants.

IDH1/2: testing in AML/cholangiocarcinoma when targeted inhibitors are therapeutic options.

FLT3 (ITD/TKD): testing in AML to guide FLT3 inhibitor use and transplant consideration.

NPM1, CEBPA, TP53, RUNX1, ASXL1: myeloid gene testing for prognosis and transplant planning in AML/MDS.

MSI/MMR: testing for mismatch repair deficiency in colorectal and other cancers to guide immunotherapy.

BRCA1/2 tumor testing: when results will influence PARP inhibitor therapy decisions; germline confirmation required for hereditary implications.

PD-L1/IHC and other protein biomarkers: used per tumor-specific guidelines alongside molecular testing.

HLA Typing for Transplantation

HLA Typing for Transplantation — Use established HLA typing methods for donor-recipient matching in allogeneic transplant scenarios; testing must be ordered by transplant teams and documented in transplant planning.

ALL of the following

HLA typing for donor selection is medically necessary when part of pre-transplant evaluation for hematologic malignancy patients considered for allogeneic hematopoietic cell transplantation.

Hematologic MRD Testing

Hematologic MRD Testing — Medically Necessary when used to assess remission status, risk of relapse, or to guide post-remission therapy per disease-specific guidelines and validated assays.

ALL of the following

MRD assays must be disease- and assay-validated (e.g., flow cytometry, PCR, NGS MRD panels) and ordered in contexts with evidence-based interpretation and management pathways (e.g., AML, ALL, CLL).
MRD testing results will be used to guide therapy intensification, de-escalation, transplant decision-making, or prognostic counseling.

Evidence-Based Solid Tumor MRD Testing - Medically Necessary

Evidence-Based Solid Tumor MRD Testing — Medically Necessary scenarios include analytically and clinically validated assays (e.g., Signatera, Guardant), and specific use-cases where prospective evidence supports clinical utility.

ANY of the following

Post-operative monitoring: validated tumor-informed MRD assay (e.g., Signatera) for colorectal cancer stage II-III after curative-intent resection when results will change adjuvant therapy decisions or surveillance intensity.
ctDNA assays with demonstrated clinical utility in specific tumor types and indications where prospective trial evidence or guideline support exists (e.g., certain colorectal MRD applications).
Use of validated plasma-based MRD assays (e.g., Guardant) as specified by evidence and labeling for particular tumor types and clinical scenarios where they alter management.

Evidence-Based Solid Tumor MRD Testing - Investigational

Evidence-Based Solid Tumor MRD Testing — Investigational when assays are unvalidated or used in tumor types/contexts without demonstrated clinical utility.

ALL of the following

MRD assays used for surveillance in tumor types without supportive evidence that detection of ctDNA/MRD alters outcomes or management decisions are investigational.

Emerging Evidence Solid Tumor MRD Testing - Investigational

Emerging Evidence Solid Tumor MRD Testing — Investigational when evidence is preliminary and not sufficient to support routine clinical use across tumor types.

ALL of the following

Use of MRD assays in expanded indications without prospective clinical validation demonstrating improved patient outcomes is investigational.

HPV-Related Solid Tumor MRD Testing (0356U)

HPV-Related Solid Tumor MRD Testing (0356U) — Use per evidence and tumor-specific indications (e.g., HPV ctDNA for surveillance in oropharyngeal cancer) when validated and clinically actionable.

ALL of the following

HPV-related ctDNA MRD assays are medically necessary when validated for the specific tumor type and when results will alter surveillance or treatment decisions as supported by evidence.

Tumor Mutational Burden (TMB) Testing (81479)

Tumor Mutational Burden (TMB) Testing (81479) — Coverage references and thresholds.

ALL of the following

TMB testing may be medically necessary when used to predict response to immune checkpoint inhibitors in tumor types where evidence supports TMB as a biomarker and when alternative, validated biomarkers (e.g., MSI) are not definitive.
Where used, a commonly referenced threshold is TMB-high >=10 mutations/megabase, recognizing that thresholds and clinical interpretations may vary by tumor type and assay platform; clinical context and test validation must guide interpretation.
TMB testing is investigational when used in tumor types or settings without evidence linking TMB levels to benefit from immunotherapy or when assay analytic validity is unproven.

Red Blood Cell Genotyping in Multiple Myeloma

Red Blood Cell Genotyping in Multiple Myeloma — Use-case related to patients receiving anti-CD38 monoclonal antibody therapy (e.g., daratumumab) where standard serologic crossmatching is confounded.

ALL of the following

Red blood cell genotyping is medically necessary for transfusion support planning in patients with multiple myeloma receiving anti-CD38 therapy when serologic testing is unreliable due to pan-reactive antibodies and genotyping will guide safe transfusion selection.
Documentation should note anti-CD38 exposure and the need for genotype-guided compatibility testing to avoid transfusion delays or adverse events.

Cancer Exome and Genome Sequencing - Investigational; Specimen Identity Testing

Cancer Exome and Genome Sequencing & Specimen Identity Testing — Investigational unless specific clinical utility is established for the indication and analytic validation is demonstrated. Genetic testing to confirm specimen identity is investigational when billed separately from required diagnostic testing.

ALL of the following

Whole-exome and whole-genome tumor sequencing are investigational for routine clinical care when used for broad discovery without demonstrated clinical utility that changes management; may be considered in research or selected complex cases with documented rationale and informed consent.
Cancer exome/genome assays must have demonstrated analytic validity, clinical validity, and established pathways for result interpretation to be considered medically necessary.
Genetic testing to confirm identity of laboratory specimens is considered investigational and not separately reimbursable when performed solely to verify specimen labeling unless explicitly required by regulatory or institutional policy and documented in the medical record.

Policy Revisions and Criteria expansions (summary)

Policy Revisions and Criteria Expansions: summary of key changes and additions in this version.

Expanded and clarified criteria for myeloid-focused broad molecular profiling panels including explicit examples of genes and clinical scenarios (AML, MDS, pre-transplant assessment).

Added and clarified MRD testing sections separating evidence-based indications (e.g., Signatera, Guardant) from investigational and emerging-use cases across solid tumors.

Clarified TMB coverage language including commonly referenced threshold (>=10 mutations/Mb) and caveats about platform and tumor-type variability.

Added guidance on red blood cell genotyping for transfusion management in multiple myeloma patients receiving anti-CD38 therapy.

Stated investigational status for routine clinical use of tumor whole-exome and whole-genome sequencing and for specimen-identity genetic testing billed separately.

Expanded tumor-specific variant analysis examples listing numerous gene-level medically necessary statements for both solid tumors and hematologic malignancies.

Summary of Revisions / New or Updated Criteria

Summary of Revisions / New or Updated Criteria: consolidated highlights for clinicians and billing staff.

New: explicit myeloid panel indications and repeat-testing guidance for hematologic malignancies.

Updated: MRD testing stratified into evidence-based, investigational, and emerging evidence categories; includes test-specific references for Signatera and Guardant where applicable.

Updated: TMB testing guidance with commonly used threshold and requirement for assay validation and tumor-type context.

New: RBC genotyping guidance for MM patients on anti-CD38 therapy to ensure safe transfusion management.

Clarified: Whole-exome/genome tumor sequencing and separate specimen-identity genetic testing are investigational for routine clinical use.

Use panel codes that align with the test scope and methodology

Verify test code reflects tumor-only vs tumor-normal paired testing

Documentation Required

Document prior testing and treatment status

Document prior molecular testing, treatment history, and current disease status in the medical record when requesting molecular profiling. If prior testing was negative or non-diagnostic, include those results in the submission; prior negative results should be documented when applicable.

Record prior molecular tests and results (including negative or indeterminate findings)
Document prior lines of therapy, current disease status, and rationale for repeat or expanded testing

Billing Rule

Do not bill specimen identity testing separately

Specimen identity or verification testing (e.g., to confirm that tumor and normal specimens are from the same individual) should not be billed separately when included as part of the overall molecular profiling service.

81265
81266
81479

Documentation Required

Follow guideline-specified indications

Align testing requests with guideline-specified indications (for example NCCN and FDA companion diagnostic indications) and applicable LCD guidance. Ensure the requested panel and the genes or biomarkers being assayed are justified by the clinical indication and consistent with national guidance.

Follow NCCN/FDA indications for biomarker testing and companion diagnostics
Align requests to relevant LCDs when present

Prior Authorization

MRD testing frequency and coverage

For measurable/minimal residual disease (MRD) testing, coverage and frequency should follow guideline recommendations and any applicable LCDs. Concert default frequency thresholds (e.g., testing frequency limits used by Concert for authorization) must be met and documentation should show alignment with guideline/LCD-specified intervals and clinical utility for the individual patient.

Concert default frequency thresholds must be met
Ensure MRD testing interval aligns with LCDs and professional guidelines
Provide clinical rationale for additional or more frequent testing

Documentation Required

HLA typing for transplant candidates

For transplant candidates, HLA typing requests must document the clinical indication and report the required loci. Report at minimum HLA-A, HLA-B (including Bw4/Bw6 where applicable) and HLA-DR.

Required loci to report: A, B, Bw4, Bw6, DR
Document transplant candidate status and urgency

Denial Risk

Coverage contingent on guideline/validation evidence

Coverage for molecular tests is contingent upon demonstration of clinical validity and clinical utility consistent with MolDX, CMS, and guideline determinations. Tests lacking sufficient evidence of analytical/clinical validity or clinical utility per MolDX/CMS or not supported by guideline recommendations may be denied as not medically necessary.

Tests without established clinical validity/utility per MolDX or CMS may be denied
Provide evidence of validation and guideline support when available

Billing Rule

Use updated CPT codes per policy reference table

Use the updated CPT codes referenced in the policy when billing molecular tests. Examples of codes added or clarified in this policy include 0422U, 81455, 81457, 81458, 81459, and 0297U. Examples of codes removed or deprecated in this update include 81449, 0211U, 0329U, 0079U, and 0111U. Confirm the current CPT descriptor and the code_group mapping before claim submission.

Added/updated example codes: 0422U, 81455, 81457-81459, 0297U
Removed/deprecated example codes: 81449, 0211U, 0329U, 0079U, 0111U

Documentation Required

AABB RBC genotyping consideration for anti-CD38 therapy

For patients receiving anti-CD38 therapies (e.g., daratumumab), consider baseline AABB-recommended red blood cell genotyping where clinically relevant to anticipate serologic testing interference. Document the rationale for baseline genotype consideration in the medical record.

Consider baseline RBC genotype per AABB guidance when anti-CD38 therapy is planned or ongoing
Document baseline genotype rationale in the chart

Prior Authorization

Prior authorization may be required per Health Plan

Prior authorization may be required by the Health Plan for molecular profiling tests. Follow plan-level prior authorization procedures, obtain necessary pre-certification when required, and supply clinical documentation (indications, prior testing, treatment history, and guideline support) to support medical necessity.

Follow Health Plan-specific PA workflows
Supply clinical documentation: indication, prior tests/results, treatment history, and guideline/LCD support

Source	Purpose/Quote
NCCN guidance examples
Multiple NCCN guidelines (eg, NSCLC, Colon, Gastric, Pancreatic, Prostate, etc.) recommend comprehensive/broad somatic testing and repeat profiling per disease stage and progression; guidance summarized across multiple tumor-specific sections (see policy Background and Rationale).
ASCO provisional opinion
ASCO Provisional Clinical Opinion (2022): perform fusion testing in metastatic/advanced solid tumors when fusion-targeted therapies are approved for that disease; test for other fusions if large panel DNA sequencing is negative.
CMS MolDX LCD
MolDX: Minimal Residual Disease Testing for Cancer (L38779) and related Billing/Coding article (A58376): MRD tests reasonable/necessary when patient has personal history within intended use, recurrence/progression would change management, and test demonstrates molecular recurrence before clinical/radiographic evidence with adequate sensitivity/specificity.
FDA KEYTRUDA label (pembrolizumab)
FDA KEYTRUDA label: defines TMB-High (TMB-H) as ≥10 mutations/megabase (mut/Mb) and indicates pembrolizumab for unresectable or metastatic TMB-H solid tumors after progression with no satisfactory alternatives; notes safety/effectiveness not established for pediatric CNS TMB-H.
AABB bulletin
AABB Association Bulletin #16-02 (updated Apr 2023): consider baseline RBC phenotype and genotype prior to initiation of anti-CD38 monoclonal antibody treatment (daratumumab or isatuximab) to mitigate interference with serologic testing; genotyping may be performed after treatment initiation.
Primary guideline source (NCCN compendium / references)
Multiple NCCN guideline sections (listed in policy references) provide tumor- and biomarker-specific testing recommendations and are cited throughout the policy (see References list and Background/Rationale).

Broad RNA Fusion Panels guidance / 'Guideline recommendations summarized'

Guideline recommendations summarized:

Broad RNA Fusion Panels guidance: Perform fusion testing in patients with metastatic or advanced solid tumors when there are fusion-targeted therapies with regulatory approval for that specific disease (NCCN provisional clinical opinion 2022). Test for other fusions in patients with metastatic or advanced solid tumors if no oncogenic driver alterations are identified on large panel DNA sequencing (NCCN provisional clinical opinion 2022). NCCN recommends comprehensive NGS testing for gene fusions and pathogenic mutations at diagnosis for Acute Lymphoblastic Leukemia and Pediatric ALL.

ref

Somatic genomic profiling: Testing of tumor tissue (or circulating tumor DNA/CTCs) to identify somatic mutations, TMB, MSI, and gene fusions for diagnostic, prognostic, and therapeutic purposes.

MRD: Measurable (minimal) residual disease monitoring to detect disease recurrence or response to therapy; MRD may be detected by molecular DNA/RNA tests (NGS, PCR, etc.).

Tumor mutational burden (TMB): A measurement of mutations carried by tumor cells that is a predictive biomarker being studied for association with response to immunotherapy; TMB-H is defined per FDA label as ≥10 mutations/megabase (mut/Mb).

Advanced cancer: Cancer that is unlikely to be cured or controlled with treatment; may have spread to nearby tissue, lymph nodes, or distant parts of the body.

Myeloproliferative neoplasms (MPN): Rare overlapping blood diseases in which bone marrow makes too many red blood cells, white blood cells, or platelets (examples: CML, PV, PMF, ET, chronic neutrophilic leukemia, chronic eosinophilic leukemia, MPN-U).

Myelodysplastic syndromes (MDS): Group of disorders with bone marrow abnormalities leading to low numbers of blood cells (WHO recognizes multiple subtypes).

Widely metastatic cancer: A cancer for which local control cannot be delivered to all areas of disease (per NCCN).

added (coding)

Added CPT codes 81457, 81458, 81459 to Tumor-Type Agnostic Solid Tumor Molecular Profiling criteria.

replaced_codes

Replaced multiple prior codes (examples: 81449 entries removed and 81455 added; 0211U replaced with 0379U; 0329U replaced with 0297U).

added

Added Targeted and Broad RNA Fusion Panel tests and coverage for Broad RNA Fusion Panels in acute lymphoblastic leukemia.

revised (coverage)

Expanded and clarified tumor-type specific coverage criteria (TMB, MSI, numerous gene-specific variant analyses) to align with updated NCCN guideline versions.

removed

Removed Tumor Specific RET Variant Analysis content and other listed codes/content (e.g., 0079U).

clarified

Reworded and clarified multiple criteria (e.g., MPN panel gene list changed to minimum JAK2, CALR, MPL).

added

HPV-Related Solid Tumor MRD Testing: new LCD-aligned criteria; investigational exclusion removed.

added

Evidence-Based Solid Tumor MRD Testing: new LCD-aligned criteria set with updated covered tumor types for Signatera and surveillance clarifications.

added

Emerging Evidence Solid Tumor MRD Testing: new investigational criteria for MRD tests without established clinical validity.

revised (TMB)

Tumor Mutational Burden criteria replaced tumor-specific lists with broader indication: any recurrent/refractory/metastatic or advanced stage III/IV cancer (excluding CNS) with progression on prior treatment and no satisfactory options.

revised

Tumor Specific BRAF, CEBPA, BRCA1/2, ESR1, FLT3, MLH1, and other gene-specific criteria updated/expanded per NCCN; multiple semantic and operational clarifications applied.

added

HLA Typing for Transplantation: new criteria set created; investigational criterion removed.