2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Evaluating variants in a biobank population using structured evidence from prior classifications (PS1, PM5, and PVS1 criteria)

Evaluating variants in a biobank population using structured evidence from prior classifications (PS1, PM5, and PVS1 criteria)

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The document appears to discuss the limitations and future work related to evaluating variants in a biobank population using structured evidence from prior classifications. The researchers analyzed three interpretation criteria (PS1, PM5, PVS1) from the ACMG/AMP Sequence Variant Interpretation guidelines and found that rules utilizing prior variant classifications may be underutilized in variant assessment. They observed that a significant percentage of ClinVar variants classified as uncertain or conflicting (VUS) had the same substitution as a pathogenic variant (PS1) or a different substitution in the same codon position (PM5). They also identified a large number of VUS and unclassified variants with evidence of pathogenicity in actionable disease genes.<br /><br />The researchers provided pre-computed lists of variants in ClinVar and exome-wide that have PS1/PM5/PVS1 evidence. They noted that it may be beneficial to consider benign evidence analogous to PS1 and PM5 in guidelines. Additionally, they found that a considerable number of individuals in the Mass General Brigham Biobank carry a VUS with PS1, PM5, or PVS1 evidence of pathogenicity in an ACMG SF gene.<br /><br />Future work mentioned in the document includes calibrating PS1, PM5, and PVS1 evidence, extending the analysis to other automatable guidelines, and evaluating phenotype enrichment in the UK Biobank. They also found that VUS with PVS1 evidence are often classified as high confidence by LOFTEE, suggesting their potential impact.<br /><br />The document emphasizes that the variants of uncertain significance and unclassified variants identified in the study will require reclassification by clinical laboratories.

Asset Subtitle

Presenting Author - Vineel Bhat, -; Co-Author - Christopher A. Cassa, PhD;

Meta Tag

Bioinformatics

Databases

Genetic Testing

Risk Assessment

Co-Author Christopher A. Cassa, PhD

Presenting Author Vineel Bhat, -

Keywords

biobank population

structured evidence

prior classifications

ACMG/AMP guidelines

variant assessment

ClinVar variants

uncertain/conflicting

pathogenic variant

actionable disease genes

reclassification