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A.2.04.102
Whole exome sequencing (WES) sequences the portion of the genome that contains protein-coding DNA, while whole genome sequencing (WGS) sequences both coding and noncoding regions of the genome. Whole exome sequencing and WGS have been proposed for use in patients presenting with disorders and anomalies not explained by standard clinical workup. Potential candidates for WES and WGS include patients who present with a broad spectrum of suspected genetic conditions.
Whole Exome Sequencing and Whole Genome Sequencing
Whole exome sequencing (WES) is targeted next-generation sequencing of the subset of the human genome that contains functionally important sequences of protein-coding DNA, while whole genome sequencing (WGS) uses next-generation sequencing (NGS) techniques to sequence both coding and non-coding regions of the genome. Whole exome sequencing and WGS have been proposed for use in patients presenting with disorders and anomalies not explained by standard clinical workup. Potential candidates for WES and WGS include patients who present with a broad spectrum of suspected genetic conditions.
Given the variety of disorders and management approaches, there are a variety of potential health outcomes from a definitive diagnosis. In general, the outcomes of a molecular genetic diagnosis include (1) impacting the search for a diagnosis, (2) informing follow-up that can benefit a child by reducing morbidity, and (3) affecting reproductive planning for parents and potentially the affected patient.
The standard diagnostic workup for patients with suspected Mendelian disorders may include combinations of radiographic, electrophysiologic, biochemical, biopsy, and targeted genetic evaluations. The search for a diagnosis may thus become a time-consuming and expensive process.
Whole Exome Sequencing and Whole Genome Sequencing Technology
Whole exome sequencing or WGS using next-generation sequencing technology can facilitate obtaining a genetic diagnosis in patients efficiently. Whole exome sequencing is limited to most of the protein-coding sequence of an individual (approximately 85%), is composed of about 20,000 genes and 180,000 exons (protein-coding segments of a gene), and constitutes approximately 1% of the genome. It is believed that the exome contains about 85% of heritable disease-causing variants. Whole exome sequencing has the advantage of speed and efficiency relative to Sanger sequencing of multiple genes. Whole exome sequencing shares some limitations with Sanger sequencing. For example, it will not identify the following: intronic sequences or gene regulatory regions; chromosomal changes; large deletions; duplications; or rearrangements within genes, nucleotide repeats, or epigenetic changes. Whole genome sequencing uses techniques similar to WES, but includes noncoding regions. Whole genome sequencing has a greater ability to detect large deletions or duplications in protein-coding regions compared with WES, but requires greater data analytics.
Technical aspects of WES and WGS are evolving, including the development of databases such as the National Institutes of Health’s ClinVar database ( http://www.ncbi.nlm.nih.gov/clinvar/ ) to catalog variants, uneven sequencing coverage, gaps in exon capture before sequencing, and difficulties with narrowing the large initial number of variants to manageable numbers without losing likely candidate disease-associated variants. The variability contributed by the different platforms and procedures used by different clinical laboratories offering exome sequencing as a clinical service is unknown.
In 2013, the American College of Medical Genetics and Genomics, Association for Molecular Pathology, and College of American Pathologists convened a workgroup to standardize terminology for describing sequence variants. In 2015, guidelines developed by this workgroup describe criteria for classifying pathogenic and benign sequence variants based on 5 categories of data: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Whole exome sequencing or WGS tests as a clinical service are available under the auspices of the CLIA. Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Standard whole exome sequencing, with trio testing when possible (see Policy Guidelines), may be considered medically necessary for the evaluation of unexplained congenital or neurodevelopmental disorders in children when ALL of the following criteria are met:
Documentation that the individual has been evaluated by a clinician with expertise in clinical genetics, including at minimum a family history and phenotype description, and counseled about the potential risks of genetic testing.
There is potential for a change in management and clinical outcome for the individual being tested.
A genetic etiology is considered the most likely explanation for the phenotype despite previous genetic testing (eg, chromosomal microarray analysis and/or targeted single-gene testing), OR when previous genetic testing has failed to yield a diagnosis, and the affected individual is faced with invasive procedures or testing as the next diagnostic step (eg, muscle biopsy).
Rapid whole exome sequencing or rapid whole genome sequencing, with trio testing when possible (see Policy Guidelines), may be considered medically necessary for the evaluation of critically ill infants in neonatal or pediatric intensive care with a suspected genetic disorder of unknown etiology when BOTH of the following criteria are met:
At least one of the following criteria is met:
Multiple congenital anomalies (see Policy Guidelines);
An abnormal laboratory test or clinical features suggests a genetic disease or complex metabolic phenotype (see Policy Guidelines);
An abnormal response to standard therapy for a major underlying condition;
None of the following criteria apply regarding the reason for admission to intensive care:
An infection with normal response to therapy;
Isolated prematurity;
Isolated unconjugated hyperbilirubinemia;
Hypoxic Ischemic Encephalopathy;
Confirmed genetic diagnosis explains illness;
Isolated Transient Neonatal Tachypnea; or
Nonviable neonates.
Whole exome sequencing is considered investigational for the diagnosis of genetic disorders in all other situations.
Repeat whole exome sequencing for the diagnosis of genetic disorders, including re-analysis of previous test results, is considered investigational.
Whole genome sequencing is considered investigational for the diagnosis of genetic disorders in all other situations.
Whole exome sequencing and whole genome sequencing are considered investigational for screening for genetic disorders.
None
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
The policy statements are intended to address the use of whole exome and whole genome sequencing for the diagnosis of genetic disorders in individuals with suspected genetic disorders and for population-based screening.
This policy does not address the use of whole exome and whole genome sequencing for preimplantation genetic diagnosis or screening, prenatal (fetal) testing, or testing of cancer cells.
Rapid Sequencing
In the NSIGHT1 trial, rapid Whole Genome Sequencing (rWGS) provided time to provisional diagnosis by 10 days with time to final report of approximately 17 days although the trial required confirmatory testing of WGS results which lengthened the time to rWGS diagnosis by 7 to 10 days. The WGS was performed in 'rapid run' mode with a minimum depth of 90 Gb per genome and average depth of coverage of 40-fold.
For rapid WES or WGS, the individual should be critically ill and in the neonatal or pediatric intensive care units (NICU, PICU) when the test is ordered but may be discharged before results are delivered.
Copy number variation (CNV) analysis should be performed in parallel with rWGS using chromosomal microarray analysis (CMA) or directly within rWGS if the test is validated for CNV analysis.
Examples of specific malformations highly suggestive of a genetic etiology, include but are not limited to any of the following:
Choanal atresia
Coloboma
Hirschsprung disease
Meconium ileus
Examples of an abnormal laboratory test suggesting a genetic disease or complex metabolic phenotype, include but are not limited to any of the following:
Abnormal newborn screen
Conjugated hyperbilirubinemia not due to total parental nutrition (TPN) cholestasis
Hyperammonemia
Lactic acidosis not due to poor perfusion
Refractory or severe hypoglycemia
Examples of clinical features suggesting a genetic disease include but not limited to any of the following:
Significant hypotonia.
Persistent seizures.
Infant with high risk stratification on evaluation for a Brief Resolved Unexplained Event (BRUE) (see below) with any of the following features:
Recurrent events without respiratory infection
Recurrent witnessed seizure like events
Required Cardiopulmonary Resuscitation (CPR)
Significantly abnormal chemistry including but not limited to electrolytes, bicarbonate or lactic acid, venous blood gas, glucose, or other tests that suggest an inborn error of metabolism
Significantly abnormal electrocardiogram (ECG), including but not limited to possible channelopathies, arrhythmias, cardiomyopathies, myocarditis or structural heart disease
Family history of:
Arrhythmia
BRUE in sibling
Developmental delay
Inborn error of metabolism or genetic disease
Long QT syndrome (LQTS)
Sudden unexplained death (including unexplained car accident or drowning) in first- or second-degree family members before age 35, and particularly as an infant.
Brief Resolved Unexplained Event (BRUE)
Brief Resolved Unexplained Event (BRUE) was previously known as Apparent Life Threatening Event (ALTE). In a practice guideline from the American Academy of Pediatrics (AAP), BRUE is defined as an event occurring in an infant younger than 1 year of age when the observer reports a sudden, brief (usually less than one minute), and now resolved episode of one or more of the following:
Absent, decreased, or irregular breathing
Altered level of responsiveness
Cyanosis or pallor
Marked change in tone (hyper- or hypotonia).
A BRUE is diagnosed only when there is no explanation for a qualifying event after conducting an appropriate history and physical examination. Note: More information is available at: https://pediatrics.aappublications.org/content/137/5/e20160590
Trio Testing
The recommended option for testing when possible is testing of the child and both parents (trio testing). Trio testing increases the chance of finding a definitive diagnosis and reduces false-positive findings.
Trio testing is preferred whenever possible but should not delay testing of a critically ill individual when rapid testing is indicated. Testing of one available parent should be done if both are not immediately available and one or both parents can be done later if needed.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.
Table 1. Nomenclature to Report on Variants Found in DNA
Previous | Updated | Definition |
Mutation | Disease-associated variant | Disease-associated change in the DNA sequence |
Variant | Change in the DNA sequence | |
Familial variant | Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives |
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification | Definition |
Pathogenic | Disease-causing change in the DNA sequence |
Likely pathogenic | Likely disease-causing change in the DNA sequence |
Variant of uncertain significance | Change in DNA sequence with uncertain effects on disease |
Likely benign | Likely benign change in the DNA sequence |
Benign | Benign change in the DNA sequence |
Genetic Counseling
Genetic counseling is primarily aimed at individuals who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
04/01/2014: Approved by Medical Policy Advisory Committee.
11/10/2014: Policy title changed from "Whole Exome Sequencing" to "Whole Exome and Whole Genome Sequencing for Diagnosis of Patients With Suspected Genetic Disorders." Policy description updated to include whole genome sequencing. Policy statement updated to add whole genome sequencing as investigational for all indications.
12/31/2014: Added the following new 2015 CPT codes to the Code Reference section: 81415, 81416, 81417, 81425, 81426, and 81427.
07/22/2015: Policy title changed from "Whole Exome and Whole Genome Sequencing for Diagnosis of Patients With Suspected Genetic Disorders" to "Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders." Policy description updated regarding WGS limitations and tests. Policy statement revised to state that whole exome sequencing and whole genome sequencing are considered investigational for the diagnosis of genetic disorders. Policy guidelines updated to add that the policy statement is intended to address the use of whole exome and whole genome sequencing for diagnosis in patients with suspected genetic disorders and for population-based screening. Code Reference section updated for ICD-10.
12/16/2015: Policy description updated regarding methods of reporting findings from WES/WGS data and to add information regarding laboratory-developed tests. Policy statement unchanged. Policy guidelines updated regarding genetic counseling. Investigative definition updated.
06/07/2016: Policy number A.2.04.102 added.
09/01/2017: Policy description updated regarding using WES and WGS for patients with disorders and anomalies not explained by standard clinical workup. Added the following policy statements: 1) Whole exome sequencing (WES) may be considered medically necessary for the evaluation of unexplained congenital or neurodevelopmental disorder in children when certain criteria are met. 2) WES is considered investigational for the diagnosis of genetic disorders in all other situations. 3) Whole genome sequencing (WGS) is considered investigational for the diagnosis of genetic disorders. Last investigational statement updated to change "diagnosis" to "screening." Policy Guidelines updated regarding trio testing. Added medically necessary definition. Code Reference section updated to add medically necessary codes table. Moved CPT codes 81415, 81416, and 81417 to the Medically Necessary Codes table and added ICD-10 diagnosis code ranges F70 - F79, F80.0 - F89, and Q00.0 - Q99.9.
11/29/2017: Policy description updated. Policy statements unchanged. Policy Guidelines updated to add genetics nomenclature update.
03/27/2018: Code Reference section updated to add new CPT code 0036U, effective 04/01/2018.
10/30/2018: Policy description updated. Policy statements unchanged. Policy Guidelines updated regarding genetic counseling.
09/22/2020: Code Reference section updated to add new CPT codes 0212U, 0213U, 0214U, and 0215U, effective 10/01/2020.
01/18/2021: Policy description updated to remove information regarding WES and WGS testing services. First medically necessary statement for standard whole exome sequencing updated to include trio testing when possible. Added medically necessary statement regarding rapid whole exome sequencing or rapid whole genome sequencing with trio testing when possible for the evaluation of critically ill infants in neonatal or pediatric intensive care with a suspected genetic disorder of unknown etiology when the specified criteria are met. Revised policy statement to state that whole genome sequencing is considered investigational for the diagnosis of genetic disorders in all other situations. Policy Guidelines updated regarding rapid sequencing, brief resolved unexplained event, and trio testing. "Nervous/Mental Conditions" changed to "Mental Health Disorders."
05/25/2021: Policy reviewed; no changes.
09/29/2021: Code Reference section updated to add new CPT code 0265U and 0267U as investigational. Effective 10/01/2021.
09/12/2022: Code Reference section updated to add new CPT codes 0335U and 0336U as investigational. Effective 10/01/2022.
11/09/2022: Policy description updated. Policy statements unchanged. Policy Guidelines updated regarding genetic counseling. Code Reference section updated to add CPT code 0094U as medically necessary and CPT code 0297U as investigational.
07/10/2023: Policy description updated. Added the following policy statement: Repeat whole exome sequencing for the diagnosis of genetic disorders, including re-analysis of previous test results, is considered investigational. Policy statement and Policy Guidelines updated to change "patient" to "individual."
09/25/2023: Code Reference section updated to add new CPT code 0417U, effective 10/01/2023.
12/21/2023: Code Reference section updated to add new 2024 CPT codes 0425U and 0426U, effective 01/01/2024.
04/17/2024: Policy reviewed; no changes.
04/01/2025: Code Reference section updated to add new CPT code 0532U, effective 04/01/2025.
04/16/2025: Policy reviewed; no changes.
07/18/2025: Code Reference section updated to add new CPT code 0567U. Effective 07/01/2025.
10/01/2025: Code Reference section updated to add new ICD-10 diagnosis codes QA0.0109, QA0.011, QA0.012, QA0.0131, QA0.0139, QA0.0141, QA0.0142, QA0.0149, QA0.0151, QA0.0159, and QA0.8.
Blue Cross and Blue Shield Association Policy # 2.04.102
This may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.
Code Number | Description |
CPT-4 | |
0036U | Exome (ie, somatic mutations), paired formalin-fixed paraffin-embedded tumor tissue and normal specimen, sequence analyses |
0094U | Genome (eg, unexplained constitutional or heritable disorder or syndrome), rapid sequence analysis |
0425U | Genome (eg, unexplained constitutional or heritable disorder or syndrome), rapid sequence analysis, each comparator genome (eg, parents, siblings) |
0426U | Genome (eg, unexplained constitutional or heritable disorder or syndrome), ultra-rapid sequence analysis |
81415 | Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis |
81416 | Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator exome (eg, parents, siblings) (List separately in addition to code for primary procedure) |
81417 | Exome (eg, unexplained constitutional or heritable disorder or syndrome); re-evaluation of previously obtained exome sequence (eg, updated knowledge or unrelated condition/syndrome) |
HCPCS | |
ICD-10 Procedure | |
ICD-10 Diagnosis | |
F70 - F79 | Intellectual disabilities code range |
F80.0 - F89 | Pervasive and specific developmental disorders code range |
Q00.0 - Q99.9 | Congenital malformations, deformations, and chromosomal abnormalities |
QA0.0109QA0.011QA0.012QA0.0131QA0.0139QA0.0141QA0.0142QA0.0149QA0.0151QA0.0159QA0.8 | Neurodevelopmental disorders related to specific genetic pathogenic variants (New 10/01/2025) |
Investigational Codes
Code Number | Description |
CPT-4 | |
0212U | Rare diseases (constitutional/heritable disorders), whole genome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, proband |
0213U | Rare diseases (constitutional/heritable disorders), whole genome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, each comparator genome (eg, parent, sibling) |
0214U | Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, proband |
0215U | Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, each comparator exome (eg, parent, sibling) |
0265U | Rare constitutional and other heritable disorders, whole genome and mitochondrial DNA sequence analysis, blood, frozen and formalin-fixed paraffin-embedded (FFPE) tissue, saliva, buccal swabs or cell lines, identification of single nucleotide and copy number variants |
0267U | Rare constitutional and other heritable disorders, identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping and whole genome sequencing |
0297U | Oncology (pan tumor), whole genome sequencing of paired malignant and normal DNA specimens, fresh or formalin fixed paraffin-embedded (FFPE) tissue, blood or bone marrow, comparative sequence analyses and variant identification |
0335U | Rare diseases (constitutional/heritable disorders), whole genome sequence analysis, including small sequence changes, copy number variants, deletions, duplications, mobile element insertions, uniparental disomy (UPD), inversions, aneuploidy, mitochondrial genome sequence analysis with heteroplasmy and large deletions, short tandem repeat (STR) gene expansions, fetal sample, identification and categorization of genetic variants |
0336U | Rare diseases (constitutional/heritable disorders), whole genome sequence analysis, including small sequence changes, copy number variants, deletions, duplications, mobile element insertions, uniparental disomy (UPD), inversions, aneuploidy, mitochondrial genome sequence analysis with heteroplasmy and large deletions, short tandem repeat (STR) gene expansions, blood or saliva, identification and categorization of genetic variants, each comparator genome (eg, parent) |
0417U | Rare diseases (constitutional/heritable disorders), whole mitochondrial genome sequence with heteroplasmy detection and deletion analysis, nuclear-encoded mitochondrial gene analysis of 335 nuclear genes, including sequence changes, deletions, insertions, and copy number variants analysis, blood or saliva, identification and categorization of mitochondrial disorder-associated genetic variants |
0532U | Rare diseases (constitutional disease/hereditary disorders), rapid whole genome and mitochondrial DNA sequencing for single-nucleotide variants, insertions/deletions, copy number variations, peripheral blood, buffy coat, saliva, buccal or tissue sample, results reported as positive or negative (New 04/01/2025) |
0567U | Rare diseases (constitutional/heritable disorders), whole-genome sequence analysis combination of short and long reads, for single-nucleotide variants, insertions/deletions and characterized intronic variants, copy-number variants, duplications/deletions, mobile element insertions, runs of homozygosity, aneuploidy, and inversions, mitochondrial DNA sequence and deletions, short tandem repeat genes, methylation status of selected regions, blood, saliva, amniocentesis, chorionic villus sample or tissue, identification and categorization of genetic variants (New 07/01/2025) |
81425 | Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis |
81426 | Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator genome (eg, parents, siblings) (List separately in addition to code for primary procedure) |
81427 | Genome (eg, unexplained constitutional or heritable disorder or syndrome); re-evaluation of previously obtained genome sequence (eg, updated knowledge or unrelated condition/syndrome) |
81479 | Unlisted molecular pathology procedure |
HCPCS | |
ICD-10 Procedure | |
ICD-10 Diagnosis |
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