ACMG/AMP interpretation of BRCA1 missense variants: Structure-informed scores add evidence strength granularity to the PP3/BP4 computational evidence.

ABSTRACT: Classification of missense variants is challenging. Lacking compelling clinical and/or functional data, ACMG/AMP lines of evidence are restricted to PM2 (rarity code applied at supporting level) and PP3/BP4 (computational evidence based mostly on multiple-sequence-alignment conservation tools). Currently, the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel uses BayesDel to apply PP3/BP4 to missense variants located in the BRCA1 RING/BRCT domains. The ACMG/AMP framework does not refer explicitly to protein structure as a putative source of pathogenic/benign evidence. Here, we tested the value of incorporating structure-based evidence such as relative solvent accessibility (RSA), folding stability (ΔΔG), and/or AlphaMissense pathogenicity to the classification of BRCA1 missense variants

SUBMITTER: Ramadane-Morchadi L 

PROVIDER: S-EPMC12120176 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature