Strong Functional Data for Pathogenicity or Neutrality Classify BRCA2 DNA-binding-domain Variants of Uncertain Significance

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2021 Feb 20

PMID 33609447

Citations 26

Authors

Marcy E Richardson

Chunling Hu

Kun Y Lee

Holly LaDuca

Kelly Fulk

Kate M Durda

Ashley M Deckman

David E Goldgar

Alvaro N A Monteiro

Rohan Gnanaolivu

Steven N Hart

Eric C Polley

Elizabeth Chao

Tina Pesaran

Fergus J Couch

Affiliations

Soon will be listed here.

Abstract

Determination of the clinical relevance of rare germline variants of uncertain significance (VUSs) in the BRCA2 cancer predisposition gene remains a challenge as a result of limited availability of data for use in classification models. However, laboratory-based functional data derived from validated functional assays of known sensitivity and specificity may influence the interpretation of VUSs. We evaluated 252 missense VUSs from the BRCA2 DNA-binding domain by using a homology-directed DNA repair (HDR) assay and identified 90 as non-functional and 162 as functional. The functional assay results were integrated with other available data sources into an ACMG/AMP rules-based classification framework used by a hereditary cancer testing laboratory. Of the 186 missense variants observed by the testing laboratory, 154 were classified as VUSs without functional data. However, after applying protein functional data, 86% (132/154) of the VUSs were reclassified as either likely pathogenic/pathogenic (39/132) or likely benign/benign (93/132), which impacted testing results for 1,900 individuals. These results indicate that validated functional assay data can have a substantial impact on VUS classification and associated clinical management for many individuals with inherited alterations in BRCA2.

Citing Articles

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