CPT 81456: RNA Genomic Sequence Analysis Panel, 51+ Genes

CPT code 81456 represents a comprehensive RNA-based genomic sequence analysis panel that evaluates 51 or more genes for alterations relevant to solid organ cancers and hematolymphoid disorders. This high-complexity molecular test supports diagnostic characterization, prognostic assessment, and potential therapeutic targeting in oncology. As precision oncology expands, such multi-gene RNA panels have become clinically significant for identifying actionable alterations and informing treatment selection.

Key payers referenced include Aetna, Blue Cross Blue Shield, Cigna Health, UnitedHealthcare, and Medicare. Readers will find a concise overview of coverage considerations across major commercial payers and Medicare, comparisons to related genomic testing codes, and clinical context regarding specimen types (tumor tissue or bone marrow) and laboratory-based service settings. The publication highlights billing and coding implications for high-complexity molecular diagnostics, common clinical indications tied to solid organ neoplasms, and the role of RNA panels alongside DNA-based testing. The analysis also outlines benchmarking and policy topics relevant to nationwide payer practices and the operational impact for laboratories and pathology services.

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Billing Code Overview

CPT code 81456 describes a genomic sequence analysis panel performed on a patient specimen to evaluate RNA alterations in 51 or more genes associated with solid organ cancers or hematolymphoid (blood or lymph) disorders and cancers. The procedure involves laboratory analysis of nucleic acids (RNA) to identify sequence-level changes across a broad panel of genes relevant to oncology.

Service Type: Genomic sequence analysis (RNA panel)

Typical Site of Service: Clinical laboratory or hospital pathology/laboratory setting, using tumor tissue or bone marrow specimens collected in an appropriate clinical environment.

National Reimbursement Benchmarks

National commercial reimbursement for CPT 81456 centers near the BUCA average commercial rate of $2,715.70, with notable divergence across major carriers. Blue Cross Blue Shield shows the highest dispersion between its 25th and 75th percentiles (range $1,527.8: $3,620.20 minus $2,092.40 = $1,527.80), indicating broader variability in negotiated rates. Cigna and Aetna also display substantial spreads (Cigna P75–P25 = $2,001.80; Aetna P75–P25 = $914.40), while UnitedHealth Group presents a more compressed interquartile spread of $1,693.40.

Examining central tendency, Cigna and Blue Cross Blue Shield have higher median and mean points relative to UnitedHealth Group, which records a lower median of $1,751.80 and a mean of $2,324.10. BUCA’s mean of $2,715.70 aligns with the upper-middle marketplace position. Overall, dispersion patterns suggest Blue Cross Blue Shield and Cigna offer the widest rate variability, while UnitedHealth Group is comparatively tighter.

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CPT 81456: RNA Genomic Sequence Analysis Panel, 51+ Genes

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Billing Code Overview

Service Type: Genomic sequence analysis (RNA panel)

Typical Site of Service: Clinical laboratory or hospital pathology/laboratory setting, using tumor tissue or bone marrow specimens collected in an appropriate clinical environment.

National Reimbursement Benchmarks

National Payer Mean Reimbursement Rates

Clinical & Coding Specifications

Clinical Context

A 62-year-old patient with a newly diagnosed metastatic lung adenocarcinoma undergoes tissue biopsy of a pulmonary mass. The oncology team requests comprehensive RNA-based genomic profiling to identify actionable gene fusions, splice variants, and other RNA alterations that may guide targeted therapy and enrollment in clinical trials. The pathology laboratory receives formalin-fixed paraffin-embedded tumor tissue and performs pre-analytic specimen assessment, nucleic acid extraction, quality control, and a high-throughput RNA sequencing panel analyzing 51 or more genes. The laboratory analyst interprets RNA alteration calls, integrates findings with tumor pathology, and issues a report to the ordering oncologist. Typical workflow steps include specimen accessioning, extraction, library preparation, sequencing, bioinformatic analysis, variant interpretation, and report finalization. Typical site of service is an outpatient hospital-based pathology laboratory, independent reference molecular laboratory, or a hospital anatomic/molecular pathology department. This service supports treatment planning for solid organ neoplasms and hematolymphoid malignancies where RNA alterations inform diagnosis or targeted therapy selection.

Related Diagnoses

ICD-10 Code	Description	Clinical Relevance
`C00.0–C79.x (solid organ neoplasms)`	Solid organ neoplasms supporting medical necessity, as listed in CMS Billing & Coding Article A56867	RNA-based panel testing is indicated to detect gene fusions and RNA alterations that impact targeted therapy selection, prognosis, or diagnostic classification across a range of solid organ cancers

Related CPT Codes

CPT Code	Description	Relationship to This Procedure
`81455`	Genomic sequence analysis panel, DNA and RNA alterations, 51 or more genes	Broad DNA+RNA panel alternative; used when both DNA and RNA alterations are assayed together rather than RNA-only analysis
`81449`	Targeted genomic sequence RNA analysis panel, separate method	Smaller, targeted RNA-only panel alternative; used for focused fusion testing with fewer genes or different methodology
`81451`	Targeted genomic sequence RNA analysis panel, separate method	Another targeted RNA panel code for smaller panels or single-method assays; may be used when the test covers fewer genes than the `81456` threshold

Related Modifiers

9 rows

Modifier	Description	When to Use
22	Modifier –22 (Increased Procedural Services) is used when a reported procedure is substantially more extensive than normally required. The CPT Manual and CMS state it may be appended only when the…	- When to use: Append modifier -22 to a procedural CPT code when the service performed is substantially more extensive than the usual service described by that code — i.e., the procedure required…
26	Modifier 26 (Professional Component) identifies and bills only the professional portion of a split service — the physician’s interpretation, report, and medical judgment — when the technical…	- Use CPT Modifier -26 when you are billing only the professional component (PC) of a split‑bill eligible service—i.e., you performed the physician interpretation, medical judgment and prepared a…
52	Modifier ‑52 (Reduced Services) indicates that a service or procedure was partially reduced or omitted at the provider’s discretion, allowing reporting of the basic procedure number with a qualifier…	- Use modifier -52 when a physician or qualified health professional electively reduces or omits part of a procedure or service (for example, performing fewer required views or omitting a portion of…
59	Modifier 59 indicates a distinct procedural service when two procedures that are not normally billed together are clinically and procedurally separate. The CPT definition (as reiterated by CMS)…	- Use modifier -59 to report a distinct procedural service when documentation supports that the procedure reported is not normally billed together with another service on the same day because of a…
62	Modifier 62 indicates that two surgeons function as co‑surgeons, each performing distinct parts of the same primary surgical procedure. It is appended to the primary procedure code (and any…	- Use modifier -62 when two surgeons act as co‑surgeons (both primary surgeons) on a single definitive primary procedure, each performing distinct parts of the same surgical procedure (append -62 to…
78	CPT modifier -78 indicates an unplanned, related return to the operating or procedure room by the same provider during the global postoperative period. It is appended when treatment for a…	- Use modifier -78 when an unplanned, related complication during the original procedure’s global postoperative period requires the patient to return to a formal operating or procedure room and the…
80	CPT® Modifier 80 (Assistant Surgeon) is appended to a surgical CPT code when a physician (MD or DO) provides full, continuous assistance throughout the operative procedure. It is intended only for…	- Use CPT Modifier -80 when a physician (MD or DO) serves as an assistant surgeon and provides full, continuous assistance throughout the entire operative procedure; append -80 to the surgical CPT…
82	Modifier 82 is appended to a surgical CPT code to indicate that an attending physician acted as an assistant because a qualified resident surgeon was unavailable. In teaching hospitals it documents…	- When to use: Append modifier 82 in teaching-hospital settings to indicate a physician served as an assistant surgeon because a qualified resident surgeon was unavailable (includes situations where…
90	Modifier ‑90 (Reference/Outside Laboratory) indicates that a laboratory test was performed by an entity other than the treating or reporting provider. The American Medical Association defines…	- Use CPT modifier -90 when a laboratory test is performed by an outside/reference laboratory (an entity other than the treating or reporting physician or qualified professional) and the claim needs…

Related Provider Taxonomies

8 rows

Taxonomy Code	Specialty	Notes
207ZP0102X	Anatomic Pathology & Clinical Pathology Physician	A pathologist deals with the causes and nature of disease and contributes to diagnosis, prognosis and treatment through knowledge gained by the labora…
207ZP0105X	Clinical Pathology/Laboratory Medicine Physician	A pathologist deals with the causes and nature of disease and contributes to diagnosis, prognosis and treatment through knowledge gained by the labora…
207L00000X	Anesthesiology Physician	An anesthesiologist is trained to provide pain relief and maintenance, or restoration, of a stable condition during and immediately following an opera…
163WX0200X	Oncology Registered Nurse	Nursing Service Providers · Registered Nurse
207ZP0213X	Pediatric Pathology Physician	A pediatric pathologist is expert in the laboratory diagnosis of diseases that occur during fetal growth, infancy and child development. The practice …
222Z00000X	Orthotist	A health care professional who is specifically educated and trained to manage comprehensive orthotic patient care, including musculoskeletal and neuro…
207ZC0008X	Clinical Informatics (Pathology) Physician	Physicians who practice Clinical Informatics collaborate with other health care and information technology professionals to analyze, design, implement…
163WC1500X	Community Health Registered Nurse	Nursing Service Providers · Registered Nurse

Related Codes

CPT-81410-GENOMIC-PANEL-AORTIC-DISEASE

CPT 81410: Genomic Sequencing Panel for Aortic Dysfunction

CPT-81411-GENETIC-DUPLICATION-DELETION-PANEL-AORTIC-DISEASE

CPT 81411: Genetic Duplication/Deletion Panel for Aortic Disease

CPT-81412-ASHKENAZI-JEWISH-GENOMIC-SEQUENCE-PANEL

CPT 81412: Ashkenazi Jewish Multi-Gene Genomic Sequence Panel

CPT-81413-GENOMIC-PANEL-CARDIAC-ION-CHANNELOPATHIES

CPT 81413: Genomic Panel for Cardiac Ion Channelopathies

CPT-81414-CARDIAC-ION-CHANNELOPATHY-CNV-PANEL

CPT 81414: Cardiac Ion Channelopathy CNV Panel

CPT-81415-EXOME-SEQUENCE-ANALYSIS-UNEXPLAINED-DISORDER

CPT 81415: Exome Sequence Analysis for Unexplained Disorders

CPT-81416-FAMILIAL-EXOME-SEQUENCE-ANALYSIS

CPT 81416: Familial Exome Sequence Analysis for Diagnostic Comparison

CPT-81417-EXOME-SEQUENCE-REEVALUATION

CPT 81417: Reanalysis of Existing Exome Sequence

CPT-81418-PHARMACOGENOMIC-MULTIGENE-DRUG-METABOLISM-PANEL

CPT 81418: Pharmacogenomic Multigene Drug-Metabolism Panel

CPT-81419-GENOMIC-SEQUENCE-PANEL-EPILEPSY

CPT 81419: Genomic Sequence Analysis Panel for Epilepsy

Showing 1–10 of 43

References

1.CPT® Codes and Descriptions. AAPC. Retrieved Aug 11, 2026.Maintains the CPT code set's official descriptions and guidelines, licensed from the American Medical Association, used as the definitional source for CPT codes on this page.
2.HCPCS Quarterly Update. Centers for Medicare & Medicaid Services (CMS). Retrieved Aug 11, 2026.CMS's quarterly release of HCPCS Level II codes and short/long descriptors, the source for HCPCS code definitions and update history.
3.ICD-10-CM Full Code List. Centers for Medicare & Medicaid Services (CMS). Retrieved Aug 11, 2026.CMS's complete ICD-10-CM diagnosis code list, used to cross-reference diagnosis codes associated with this procedure or service.

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Clinical & Coding Specifications

Clinical Context

Related Diagnoses

ICD-10 Code	Description	Clinical Relevance
`C00.0–C79.x (solid organ neoplasms)`	Solid organ neoplasms supporting medical necessity, as listed in CMS Billing & Coding Article A56867	RNA-based panel testing is indicated to detect gene fusions and RNA alterations that impact targeted therapy selection, prognosis, or diagnostic classification across a range of solid organ cancers

Related CPT Codes

CPT Code	Description	Relationship to This Procedure
`81455`	Genomic sequence analysis panel, DNA and RNA alterations, 51 or more genes	Broad DNA+RNA panel alternative; used when both DNA and RNA alterations are assayed together rather than RNA-only analysis
`81449`	Targeted genomic sequence RNA analysis panel, separate method	Smaller, targeted RNA-only panel alternative; used for focused fusion testing with fewer genes or different methodology
`81451`	Targeted genomic sequence RNA analysis panel, separate method	Another targeted RNA panel code for smaller panels or single-method assays; may be used when the test covers fewer genes than the `81456` threshold

Related Modifiers

9 rows

Modifier	Description	When to Use
22	Modifier –22 (Increased Procedural Services) is used when a reported procedure is substantially more extensive than normally required. The CPT Manual and CMS state it may be appended only when the…	- When to use: Append modifier -22 to a procedural CPT code when the service performed is substantially more extensive than the usual service described by that code — i.e., the procedure required…
26	Modifier 26 (Professional Component) identifies and bills only the professional portion of a split service — the physician’s interpretation, report, and medical judgment — when the technical…	- Use CPT Modifier -26 when you are billing only the professional component (PC) of a split‑bill eligible service—i.e., you performed the physician interpretation, medical judgment and prepared a…
52	Modifier ‑52 (Reduced Services) indicates that a service or procedure was partially reduced or omitted at the provider’s discretion, allowing reporting of the basic procedure number with a qualifier…	- Use modifier -52 when a physician or qualified health professional electively reduces or omits part of a procedure or service (for example, performing fewer required views or omitting a portion of…
59	Modifier 59 indicates a distinct procedural service when two procedures that are not normally billed together are clinically and procedurally separate. The CPT definition (as reiterated by CMS)…	- Use modifier -59 to report a distinct procedural service when documentation supports that the procedure reported is not normally billed together with another service on the same day because of a…
62	Modifier 62 indicates that two surgeons function as co‑surgeons, each performing distinct parts of the same primary surgical procedure. It is appended to the primary procedure code (and any…	- Use modifier -62 when two surgeons act as co‑surgeons (both primary surgeons) on a single definitive primary procedure, each performing distinct parts of the same surgical procedure (append -62 to…
78	CPT modifier -78 indicates an unplanned, related return to the operating or procedure room by the same provider during the global postoperative period. It is appended when treatment for a…	- Use modifier -78 when an unplanned, related complication during the original procedure’s global postoperative period requires the patient to return to a formal operating or procedure room and the…
80	CPT® Modifier 80 (Assistant Surgeon) is appended to a surgical CPT code when a physician (MD or DO) provides full, continuous assistance throughout the operative procedure. It is intended only for…	- Use CPT Modifier -80 when a physician (MD or DO) serves as an assistant surgeon and provides full, continuous assistance throughout the entire operative procedure; append -80 to the surgical CPT…
82	Modifier 82 is appended to a surgical CPT code to indicate that an attending physician acted as an assistant because a qualified resident surgeon was unavailable. In teaching hospitals it documents…	- When to use: Append modifier 82 in teaching-hospital settings to indicate a physician served as an assistant surgeon because a qualified resident surgeon was unavailable (includes situations where…
90	Modifier ‑90 (Reference/Outside Laboratory) indicates that a laboratory test was performed by an entity other than the treating or reporting provider. The American Medical Association defines…	- Use CPT modifier -90 when a laboratory test is performed by an outside/reference laboratory (an entity other than the treating or reporting physician or qualified professional) and the claim needs…

Related Provider Taxonomies

8 rows

Taxonomy Code	Specialty	Notes
207ZP0102X	Anatomic Pathology & Clinical Pathology Physician	A pathologist deals with the causes and nature of disease and contributes to diagnosis, prognosis and treatment through knowledge gained by the labora…
207ZP0105X	Clinical Pathology/Laboratory Medicine Physician	A pathologist deals with the causes and nature of disease and contributes to diagnosis, prognosis and treatment through knowledge gained by the labora…
207L00000X	Anesthesiology Physician	An anesthesiologist is trained to provide pain relief and maintenance, or restoration, of a stable condition during and immediately following an opera…
163WX0200X	Oncology Registered Nurse	Nursing Service Providers · Registered Nurse
207ZP0213X	Pediatric Pathology Physician	A pediatric pathologist is expert in the laboratory diagnosis of diseases that occur during fetal growth, infancy and child development. The practice …
222Z00000X	Orthotist	A health care professional who is specifically educated and trained to manage comprehensive orthotic patient care, including musculoskeletal and neuro…
207ZC0008X	Clinical Informatics (Pathology) Physician	Physicians who practice Clinical Informatics collaborate with other health care and information technology professionals to analyze, design, implement…
163WC1500X	Community Health Registered Nurse	Nursing Service Providers · Registered Nurse

Related Codes

CPT-81410-GENOMIC-PANEL-AORTIC-DISEASE

CPT 81410: Genomic Sequencing Panel for Aortic Dysfunction

CPT-81411-GENETIC-DUPLICATION-DELETION-PANEL-AORTIC-DISEASE

CPT 81411: Genetic Duplication/Deletion Panel for Aortic Disease

CPT-81412-ASHKENAZI-JEWISH-GENOMIC-SEQUENCE-PANEL

CPT 81412: Ashkenazi Jewish Multi-Gene Genomic Sequence Panel

CPT-81413-GENOMIC-PANEL-CARDIAC-ION-CHANNELOPATHIES

CPT 81413: Genomic Panel for Cardiac Ion Channelopathies

CPT-81414-CARDIAC-ION-CHANNELOPATHY-CNV-PANEL

CPT 81414: Cardiac Ion Channelopathy CNV Panel

CPT-81415-EXOME-SEQUENCE-ANALYSIS-UNEXPLAINED-DISORDER

CPT 81415: Exome Sequence Analysis for Unexplained Disorders

CPT-81416-FAMILIAL-EXOME-SEQUENCE-ANALYSIS

CPT 81416: Familial Exome Sequence Analysis for Diagnostic Comparison

CPT-81417-EXOME-SEQUENCE-REEVALUATION

CPT 81417: Reanalysis of Existing Exome Sequence

CPT-81418-PHARMACOGENOMIC-MULTIGENE-DRUG-METABOLISM-PANEL

CPT 81418: Pharmacogenomic Multigene Drug-Metabolism Panel

CPT-81419-GENOMIC-SEQUENCE-PANEL-EPILEPSY

CPT 81419: Genomic Sequence Analysis Panel for Epilepsy

Showing 1–10 of 43

References

1.CPT® Codes and Descriptions. AAPC. Retrieved Aug 11, 2026.Maintains the CPT code set's official descriptions and guidelines, licensed from the American Medical Association, used as the definitional source for CPT codes on this page.
2.HCPCS Quarterly Update. Centers for Medicare & Medicaid Services (CMS). Retrieved Aug 11, 2026.CMS's quarterly release of HCPCS Level II codes and short/long descriptors, the source for HCPCS code definitions and update history.
3.ICD-10-CM Full Code List. Centers for Medicare & Medicaid Services (CMS). Retrieved Aug 11, 2026.CMS's complete ICD-10-CM diagnosis code list, used to cross-reference diagnosis codes associated with this procedure or service.

Published by

Trek Health powers OpenPayer with a leading commercial payer intelligence platform, seamlessly converting fragmented payer data into actionable insights for provider organizations.