Systematic misclassification of missense variants in BRCA1 and BRCA2 “coldspots”
A partir des données de la base ClinVar et afin de réduire le nombre de variants de signification inconnue, cette étude identifie les mutations faux sens situées dans les régions des gènes BRCA1 et BRCA2 peu sensibles aux mutations
Guidelines for variant interpretation incorporate variant hotspots in critical functional domains as evidence for pathogenicity (e.g., PM1 and PP2), but do not use “coldspots,” that is, regions without essential functions that tolerate variation, as evidence a variant is benign. To improve variant classification we evaluated BRCA1 and BRCA2 missense variants reported in ClinVar to identify regions where pathogenic missenses are extremely infrequent, defined as coldspots.
Genetics in Medicine 2020