Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".

ABSTRACT:

Purpose

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.

Methods

We used Bayesian approaches to model variant classification in these regions.

Results

BRCA1 exon 11 (~60% of the coding sequence), and BRCA2 exons 10 and 11 (~65% of the coding sequence), are coldspots. Of 89 pathogenic (P) or likely pathogenic (LP) missense variants in BRCA1, none are

SUBMITTER: Dines JN 

PROVIDER: S-EPMC7200594 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature