Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels.

摘要: The 2015 American College of Medical Genetics and Genomics (ACMG) the Association for Molecular Pathology (AMP) guidelines clinical sequence variant interpretation state that “well-established” functional studies can be used as evidence in classification. These articulated key attributes data, including assays should reflect biological environment analytically sound; however, details how to evaluate these were left expert judgment. Clinical Genome Resource (ClinGen) designates Variant Curation Expert Panels (VCEPs) specific disease areas make gene-centric specifications ACMG/AMP guidelines, more definitions appropriate assays. We set out existing VCEP evaluated criteria (PS3/BS3) six VCEPs (CDH1, Hearing Loss, Inherited Cardiomyopathy-MYH7, PAH, PTEN, RASopathy). then established evaluating based on mechanism, general class assay, characteristics assay instances described primary literature. Using criteria, we extensively curated cited by each their pilot classification analyze recommendations use studies. Unsurprisingly, our analysis highlighted breadth VCEP-approved assays, reflecting diversity mechanisms among VCEPs. also noted substantial variability between method select approach specify strength modifications, well differences suggested validation parameters. Importantly, observed discrepancies parameters specified required approved fulfillment requirements individual interpretation. Interpretation intricacies often requires expert-level knowledge gene disease, current are a useful tool improve accessibility data providing starting point curators identify metrics. However, suggests further guidance is needed standardize this process ensure consistency application evidence.