Informing variant assessment using structured evidence from prior classifications (PS1, PM5, and PVS1 sequence variant interpretation criteria)

Purpose: This study aimed to explore whether evidence of pathogenicity from prior variant classifications in ClinVar could be used to inform variant interpretation using the American College of Medical Genetics and Genomics/Association for Molecular Pathology clinical guidelines.Methods: We identified distinct single-nucleotide variants (SNVs) that are either similar in location or in functional consequence to pathogenic variants in ClinVar and analyzed evidence in support of pathogenicity using 3 interpretation criteria.Results: Thousands of variants, including many in clinically actionable disease genes (American College of Medical Genetics and Genomics secondary findings v3.0), have evidence of path-ogenicity from existing variant classifications, accounting for 2.5% of nonsynonymous SNVs within ClinVar. Notably, there are many variants with uncertain or conflicting classifications that cause the same amino acid substitution as other pathogenic variants (PS1, N = 323), variants that are predicted to cause different amino acid substitutions in the same codon as pathogenic var-iants (PM5, N = 7692), and loss-of-function variants that are present in genes in which many loss-of-function variants are classified as pathogenic (PVS1, N = 3635). Most of these variants have similar computational predictions of pathogenicity and splicing effect as their associated pathogenic variants.Conclusion: Broadly, for >1.4 million SNVs exome wide, information from previously clas-sified variants could be used to provide evidence of pathogenicity. We have developed a pipeline to identify variants meeting these criteria that may inform interpretation efforts.(c) 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Automated summary

This study explores the potential of using evidence of pathogenicity from prior variant classifications in ClinVar to inform variant interpretation based on the ACMG/AMP clinical guidelines. The findings show that thousands of variants, including those in clinically actionable disease genes, have evidence of pathogenicity from existing variant classifications, accounting for 2.5% of nonsynonymous SNVs in ClinVar. These variants with evidence of pathogenicity have similar computational predictions and splicing effects as their associated pathogenic variants.