Classification of Missense Substitutions in the BRCA Genes: a Database Dedicated to Ex-UVs

Overview

Journal Hum Mutat

Specialty Genetics

Date 2011 Oct 13

PMID 21990165

Citations 42

Authors

Maxime P Vallee

Tiana C Francy

Megan K Judkins

Davit Babikyan

Fabienne Lesueur

Amanda Gammon

David E Goldgar

Fergus J Couch

Sean V Tavtigian

Affiliations

Soon will be listed here.

Abstract

Unclassified sequence variants (UVs) arising from clinical mutation screening of cancer susceptibility genes present a frustrating issue to clinical genetics services and the patients that they serve. We created an open-access database holding missense substitutions from the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2. The main inclusion criterion is that each variant should have been assessed in a published work that used the Bayesian integrated evaluation of unclassified BRCA gene variants. Transfer of data on these substitutions from the original publications to our database afforded an opportunity to analyze the missense substitutions under a single model and to remove inconsistencies that arose during the evolution of the integrated evaluation over the last decade. This analysis also afforded the opportunity to reclassify these missense substitutions according to the recently published IARC 5-Class system. From an initial set of 248 missense substitutions, 31 were set aside due to nonnegligible probability to interfere with splicing. Of the remaining substitutions, 28 fell into one of the two pathogenic classes (IARC Class 4 or 5), 174 fell into one of the two nonpathogenic classes (IARC Class 1 or 2), and 15 remain in IARC Class 3, "Uncertain." The database is available at http://brca.iarc.fr/LOVD.

Citing Articles

DNA repair function scores for 2172 variants in the BRCA1 amino-terminus.

Diabate M, Islam M, Nagy G, Banerjee T, Dhar S, Smith N PLoS Genet. 2023; 19(8):e1010739.

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DNA Repair Function Scores for 2172 Variants in the BRCA1 Amino-Terminus.

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PMID: 37090572 PMC: 10120616. DOI: 10.1101/2023.04.10.536331.

Comprehensive evaluation and efficient classification of BRCA1 RING domain missense substitutions.

Clark K, Paquette A, Tao K, Bell R, Boyle J, Rosenthal J Am J Hum Genet. 2022; 109(6):1153-1174.

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In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing.

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