Informing Variant Assessment using Structured Evidence from Prior Classifications (PS1, PM5, and PVS1 Sequence Variant Interpretation Criteria)

AbstractPurposeTo explore whether evidence of pathogenicity from prior variant classifications in ClinVar could be used to inform variant interpretation using the ACMG/AMP clinical guidelines.MethodsWe identify distinct SNVs which are either similar in location or in functional consequence to pathogenic variants in ClinVar, and analyze evidence in support of pathogenicity using three interpretation criteria.ResultsThousands of variants, including many in clinically actionable disease genes (ACMG SFv3.0), have evidence of pathogenicity from existing variant classifications, accounting for 2.5% of non-synonymous SNVs within ClinVar. Notably, there are many variants with uncertain or conflicting classifications which cause the same amino acid substitution as other pathogenic variants (PS1, N=323), variants which are predicted to cause different amino acid substitutions in the same codon as pathogenic variants (PM5, N=7,692), and LOF variants which are present in genes where many LOF variants are classified as pathogenic (PVS1, N=3,635). The majority of these variants have similar computational predictions of pathogenicity and splicing impact as their associated pathogenic variants.ConclusionBroadly, over 1.4 million SNVs exome-wide could make use of information from previously classified pathogenic variants. We have developed a pipeline to identify variants meeting these criteria, which may inform interpretation efforts.