期刊
GENOME MEDICINE
卷 11, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13073-019-0683-1
关键词
Clinical genome resource; Clinical exome sequencing; Clinical genome sequencing; Functional assays; Variant interpretation
资金
- UNC/ACMG/Geisinger/Kaiser [U41HG009650, 3U41HG009650-02S1]
- National Human Genome Research Institute (NHGRI) [U41HG009650, U41HG006834, U41HG009649]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U24HD093483, U24HD093486, U24HD093487]
- National Institute of General Medical Sciences [5T32 GM007092, 5T32 GM008719-6]
- University Cancer Research Fund
- Yang Family Biomedical Scholars Award
Background The 2015 American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines for clinical sequence variant interpretation state that well-established functional studies can be used as evidence in variant classification. These guidelines articulated key attributes of functional data, including that assays should reflect the biological environment and be analytically sound; however, details of how to evaluate these attributes were left to expert judgment. The Clinical Genome Resource (ClinGen) designates Variant Curation Expert Panels (VCEPs) in specific disease areas to make gene-centric specifications to the ACMG/AMP guidelines, including more specific definitions of appropriate functional assays. We set out to evaluate the existing VCEP guidelines for functional assays. Methods We evaluated the functional criteria (PS3/BS3) of six VCEPs (CDH1, Hearing Loss, Inherited Cardiomyopathy-MYH7, PAH, PTEN, RASopathy). We then established criteria for evaluating functional studies based on disease mechanism, general class of assay, and the characteristics of specific assay instances described in the primary literature. Using these criteria, we extensively curated assay instances cited by each VCEP in their pilot variant classification to analyze VCEP recommendations and their use in the interpretation of functional studies. Results Unsurprisingly, our analysis highlighted the breadth of VCEP-approved assays, reflecting the diversity of disease mechanisms among VCEPs. We also noted substantial variability between VCEPs in the method used to select these assays and in the approach used to specify strength modifications, as well as differences in suggested validation parameters. Importantly, we observed discrepancies between the parameters VCEPs specified as required for approved assay instances and the fulfillment of these requirements in the individual assays cited in pilot variant interpretation. Conclusions Interpretation of the intricacies of functional assays often requires expert-level knowledge of the gene and disease, and current VCEP recommendations for functional assay evidence are a useful tool to improve the accessibility of functional data by providing a starting point for curators to identify approved functional assays and key metrics. However, our analysis suggests that further guidance is needed to standardize this process and ensure consistency in the application of functional evidence.
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