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- Clinical laboratories should have separate policies and protocols for initial variant classification, variant-level reevaluation, and case-level reanalysis, which should be periodically reviewed and updated (as an example, the College of American Pathologists recommends a review of all policies and protocols at least every two years). The laboratory policies should be made available to the ordering provider upon request.
- Clinical laboratories should respond to external requests for variant-level reevaluations or case-level reanalyses in a timely manner and should have policies for addressing those requests.
- Maintaining an up-to-date database of classified variants within the clinical laboratory is critical for the provision of accurate and consistent variant classifications.
- Documentation provided by clinical laboratories (e.g., consent forms, reports) should include the possibility that clinically significant changes in variant classification will occur routinely through new discovery, enhanced clinical correlation, and functional or epidemiologic studies.
- Additional charges/fees may be warranted when the professional services of the clinical laboratory are required for the reevaluation/reanalysis of genomic data. Establishing a mechanism by which these professional services are billable and covered by payers is critical toward ensuring the long-term success of clinical genomic testing.
- In addition to issuing formal reports to clinicians, clinical laboratories should submit classified variants, as well as any reclassifications and updated phenotypic information, to public databases (e.g., ClinVar) on a regular basis. Submissions should be accompanied by a summary of the evidence supporting the classification or reclassification.
Considerations for variant-level reevaluation
- When formulating laboratory policies and protocols for variant-level reevaluation, it is reasonable to prioritize such efforts to maximize the potential clinical impact. For example, classified variants with either highly confident assertions or variants that are not currently thought to be clinically significant (i.e., those that are benign or likely benign) could be reevaluated less frequently than those with uncertain or likely pathogenic classifications.
- Routine reevaluation of a clinical laboratory’s entire internal database of variant classifications is likely to be impractical. However, a partial or automated review or a prioritization of variants for re-review may be considered in the following circumstances:
- Availability of a new community resource (e.g., gnomAD)
- Publication and/or adoption of a novel/updated methodology for variant assessment
- Publication of evidence supporting new gene–disease relationships and/or mechanisms of disease
- Upon reevaluation, any variant classified and reported prior to the implementation of the current ACMG variant classification standards should be reevaluated using the current ACMG standards.
- Use of an existing variant classification without reevaluation may be considered when the variant has previously been classified without uncertainty (pathogenic, benign) using the laboratory’s current protocol.
Considerations for case-level reanalysis
- Clinical laboratories are encouraged to request updated clinical and family history information, when available, to facilitate case-level reanalysis of genomic data. Updated information may result in the identification of additional variants that are associated with the indication(s) for testing.
- If significant improvements have been made to the bioinformatics handling of the data (alignment/variant calling and/or the annotation/automated filtering processes), the laboratory should consider (if technically possible) whether case-level reanalysis should also include reprocessing the data through the analysis pipeline to capture any potentially overlooked variants in the initial assessment.
Considerations for reporting
- Clinical laboratories should make concerted efforts to prioritize the reporting and communication of any reclassifications that may affect clinical management. For example, a variant of uncertain clinical significance that is reclassified as a likely pathogenic variant should be prioritized as compared to a likely pathogenic variant that is reclassified as a pathogenic variant. Clinical laboratories should also consider the reporting and communication of any variants of uncertain clinical significance that are reclassified to likely benign or benign, as these reclassifications may also have an impact on clinical management.
- For laboratory-initiated variant reevaluations, laboratories should have a policy regarding the release of an updated report when there is a clinically significant change in variant classification, which should include information regarding to whom the updated report is sent when the ordering health-care provider is no longer involved in the individual’s care (e.g., the provider relocates, retires, or dies; the patient changes providers).
- For clinician-initiated variant reevaluation requests, laboratories should consider communicating and reporting all updated classifications, even when the initial classification remains unchanged. For reporting purposes, an addendum to the previous report could be issued.
- Reevaluations of variants on the ACMG secondary findings gene list may also have an impact on clinical management, and the reporting and communication of all pathogenic variants (and expected pathogenic variants, if applicable) in a gene that is on the current secondary findings gene list should also be prioritized upon case reanalysis if the patient originally consented to receive this information.
Considerations for retesting
- As laboratory technology, processes, and knowledge improve, retesting individuals using new methodologies may be preferable to variant-level reevaluation or case-level reanalysis. For example, genome sequencing may be indicated for an individual with nondiagnostic results by exome sequencing.
- When considering reanalysis versus retesting, some important factors to consider include:
- The time elapsed since the previous testing occurred
- Improvements in technology/chemistry (e.g., new methods for DNA capture and sequencing)
- Bioinformatics advancements
- New information regarding the genetic etiology of a condition
- Any additional patient phenotypes or family history that developed in the interim
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David KL, Best RG, Brenman LM, et al. Patient re-contact afterrevision of genomic test results: points to consider-a statement of the AmericanCollege of Medical Genetics and Genomics (ACMG). Genet Med. 2018 Dec 22; https://www.nature.com/articles/s41436-018-0391-z [Epub ahead of print].
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