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

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.

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.

Thousands of variants, including many in clinically actionable disease genes (American College of Medical Genetics and Genomics secondary findings v3.0), have evidence of pathogenicity 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 variants (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.

Broadly, for >1.4 million SNVs exome wide, information from previously classified 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.