Highmark Commercial Medical Policy - Pennsylvania

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Medical Policy: L-206-003
Topic: Whole Exome Sequencing
Section: Laboratory
Effective Date: November 13, 2017
Issue Date: November 13, 2017
Last Reviewed: March 2017

Whole exome sequencing (WES) utilizes DNA-enrichment methods and massively parallel nucleotide sequencing to identify disease-associated variants throughout the human genome.

WES has been proposed for diagnostic use in individuals who present with complex genetic phenotypes suspected of having a rare genetic condition, who cannot be diagnosed by standard clinical workup, or when features suggest a broad differential diagnosis that would require evaluation by multiple genetic tests.

This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Policy Position Coverage is subject to the specific terms of the member’s benefit plan.

Whole exome sequencing (WES) may be considered medically necessary when ALL of the following criteria are met:

  • The patient and family history have been evaluated by a Board-Certified or Board-Eligible Medical Geneticist; and 
  • Patient is less than 21 years of age; and 
  • A genetic etiology is considered the most likely explanation for the phenotype, based on EITHER of the following:
    • Multiple congenital abnormalities defined by ONE of the following:
      • TWO or MORE major anomalies affecting different organ systems*; or
      • ONE major and TWO or MORE minor anomalies affecting different organ systems*; or 
    • TWO of the following criteria are met:
      • Abnormality affecting at minimum a single organ system; and/or
      • Significant developmental delay, intellectual disability (e.g., characterized by significant limitations in both intellectual functioning and in adaptive behavior); and/or
      • Symptoms of a complex neurodevelopmental disorder (e.g., self-injurious behavior, reverse sleep-wake cycles); and/or
      • Severe neuropsychiatric condition (e.g., schizophrenia, bipolar disorder, Tourette syndrome); and/or
      • Family history strongly suggestive of a genetic etiology, including consanguinity; and/or
      • Period of unexplained developmental regression; and/or
      • Biochemical findings suggestive of an inborn error of metabolism; and
    • Alternate etiologies have been considered and ruled out when possible (e.g., environmental exposure, injury, infection); and 
    • Clinical presentation does not fit a well-described syndrome for which single-gene or targeted panel testing (e.g., comparative genomic hybridization [CGH]/chromosomal microarray analysis [CMA]) is available; and 
    • There is a predicted impact on health outcomes including:
      • Application of specific treatments; or
      • Withholding of contraindicated treatments; or
      • Surveillance for later-onset comorbidities; or
      • Initiation of palliative care; or
      • Withdrawal of care; and
    • A diagnosis cannot be made by standard clinical work-up, excluding invasive procedures such as muscle biopsy.

*Major structural abnormalities are generally serious enough as to require medical treatment on their own (such as surgery) and are not minor developmental variations that may or may not suggest an underlying disorder.

WES is considered experimental/investigational and therefore non-covered for screening for genetic disorders in asymptomatic or pre-symptomatic individuals.

Whole Genome Sequencing (WGS) is considered experimental/investigational and therefore non-covered for all indications.

Procedure Codes
81415, 81416, 81417

WES may be considered for reimbursement when it is deemed more efficient and economical than the separate single-gene tests or panels that would be recommended based on the differential diagnosis (e.g., genetic conditions that demonstrate a high degree of genetic heterogeneity).

WES may be considered for reimbursement only when billed with an appropriate CPT code:

  • 81415 should be billed for the proband. 81415 should only be billed when analyzing the entire whole exome sequence, rather than a targeted set of genes.  At a minimum, genes associated with the clinical presentation and those constitutional mutations in genes listed on the ACMG minimum list entitled “Conditions, genes, and variants recommended for return of incidental findings in clinical sequencing” (Green et al) should be reported by the laboratory to the ordering clinician, regardless of the indication for which the exome sequence was ordered.
  • 81416 should be billed when a comparator exome is performed.  A trio of the proband and both parents is generally preferred, although other family members may be more informative based on the clinical presentation.  A maximum of two units of 81416 may be considered for reimbursement.
  • 81415 is not reimbursable for a targeted exome analysis (e.g. XomeDxSlice).  The appropriate GSP panel code, unlisted code (e.g. 81479), or Tier 1 or Tier 2 code(s) must be billed.
  • 81415 will be reimbursable once per lifetime.
  • When a single exome platform is used for more than one test (e.g., XomeDxSlice reflex to full exome analysis), all tests reported from the same exome analysis may be:
    • Billed together under one unit of 81415; or
    • Billed separately, but 81415 cannot be used.  When billed separately, studies may be billed using Tier 1 codes, Tier 2 codes, or 81479 at an amount that does not exceed the cost of full exome analysis.
  • 81417 is not an appropriate code for reflex from targeted to full exome.
  • Re-evaluation of a previously obtained exome due to updated knowledge or for the purpose of evaluating a patient for an unrelated condition/syndrome on a different date of service will be considered for reimbursement only when billed using 81417.
Professional Statements and Societal Positions

Guidelines and Evidence

The American College of Medical Genetics (ACMG, 2012) states the following regarding the clinical application of whole exome and whole genome testing:

  • “WGS/WES should be considered in the clinical diagnostic assessment of a phenotypically affected individual when:”
    • “The phenotype or family history data strongly implicate a genetic etiology, but the phenotype does not correspond with a specific disorder for which a genetic test targeting a specific gene is available on a clinical basis.”
    • “A patient presents with a defined genetic disorder that demonstrates a high degree of genetic heterogeneity, making WES or WGS analysis of multiple genes simultaneously a more practical approach.”
    • “A patient presents with a likely genetic disorder, but specific genetic tests available for that phenotype have failed to arrive at a diagnosis.”  “A fetus with a likely genetic disorder in which specific genetic tests, including targeted sequencing tests, available for that phenotype has failed to arrive at a diagnosis.”
    • “Prenatal diagnosis by genomic (i.e., next-generation whole-exome or whole-genome) sequencing has significant limitations.  The current technology does not support short turnaround times, which are often expected in the prenatal setting.  There are high rates of false positives, false negatives, and variants of unknown clinical significance. These can be expected to be significantly higher than seen when array CGH is used in prenatal diagnosis.”
  • The following are recommended pretest considerations:
    • “Pretest counseling should be done by a medical geneticist or an affiliated genetic counselor and should include a formal consent process.”
    • “Before initiating WGS/WES, participants should be counseled regarding the expected outcomes of testing, the likelihood and type of incidental results that could be generated, and what results will or will not be disclosed.”
    • “As part of the pretest counseling, a clear distinction should be made between clinical and research-based testing. In many cases, findings will include variants of unknown significance that might be the subject for research; in such instances a protocol approved by an institutional review board must be in place and appropriate prior informed consent obtained from the participant.”

The American College of Medical Genetics (ACMG, 2012) states the following regarding informed consent for whole exome and whole genome testing:

  • “Before initiating GS/ES, counseling should be performed by a medical geneticist or an affiliated genetic counselor and should include written documentation of consent from the patient.”
  • “Incidental/secondary findings revealed in either children or adults may have high clinical significance for which interventions exist to prevent or ameliorate disease severity. Patients should be informed of this possibility as a part of the informed consent process.”
  • “Pretest counseling should include a discussion of the expected outcomes of testing, the likelihood and type of incidental results that may be generated, and the types of results that will or will not be returned.  Patients should know if and what type of incidental findings may be returned to their referring physician by the laboratory performing the test.”
  • “GS/ES is not recommended before the legal age of majority except for:
    • Phenotype-driven clinical diagnostic uses;
    • Circumstances in which early monitoring or interventions are available and effective; or
    • Institutional review board–approved research.”
  • “As part of the pretest counseling, a clear distinction should be made between clinical and research-based testing.”
  • “Patients should be informed as to whether individually identifiable results may be provided to databases, and they should be permitted to opt out of such disclosure.”
  • “Patients should be informed of policies regarding re-contact of referring physicians as new knowledge is gained about the significance of particular results.”

The American College of Medical Genetics (ACMG, Updated 2016) published guidelines for the reporting of incidental findings in clinical exome and genome sequencing: They state the following:

  • “We continue to support the reporting of known or expected pathogenic variants, but we do not recommend reporting variants of uncertain significant as secondary findings (SFs).”
  • This guideline includes a table of “ACMG SF v2.0 genes and associated phenotypes recommended for return of secondary findings in clinical sequencing.”

Evidence for the clinical utility of WES in individuals with multiple congenital anomalies and/or a neurodevelopmental phenotype includes numerous large case series. Relevant outcomes include improved clinical decision-making (e.g., application of specific treatments, withholding of contraindicated treatments, changes to surveillance), changes in reproductive decision making, and resource utilization. WES serves as a powerful diagnostic tool for individuals with rare genetic conditions in which the specific genetic etiology is unclear or unidentified by standard clinical workup.

The average diagnostic yield of WES is 20-40% depending on the individual’s age, phenotype, previous workup, and number of comparator samples analyzed.  Among individuals with pathogenic or likely pathogenic findings by WES, 5-7% received a dual molecular diagnosis (i.e., two significant findings associated with non-overlapping clinical presentations).

The use of family trio WES reduces the rate of uncertain findings, adds to the clinical sensitivity with regard to the interpretation of clinically novel genes, and increases the diagnostic utility of WES.  For example, in three publications the positive rate ranges from 31-37% in patients undergoing trio analysis compared to 20-23% positive rate among proband-only WES.
Re-evaluation of previously obtained exome sequence has the potential for additional diagnostic yield because of constant expansions of existing variant databases, as well as periodic novel gene discovery.

Place of Service: Inpatient/Outpatient

Experimental/Investigational (E/I) services are not covered regardless of place of service.

WES is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.

The policy position applies to all commercial lines of business

Denial Statements

Services that do not meet the criteria of this policy will not be considered medically necessary. A network provider cannot bill the member for the denied service unless: (a) the provider has given advance written notice, informing the member that the service may be deemed not medically necessary; (b) the member is provided with an estimate of the cost; and (c) the member agrees in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.

Services that do not meet the criteria of this policy will be considered experimental/investigational (E/I). A network provider can bill the member for the experimental/investigational service. The provider must give advance written notice informing the member that the service has been deemed E/I. The member must be provided with an estimate of the cost and the member must agree in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.


Medical policies do not constitute medical advice, nor are they intended to govern the practice of medicine. They are intended to reflect Highmark's reimbursement and coverage guidelines. Coverage for services may vary for individual members, based on the terms of the benefit contract.

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