Functional Assays for Analysis of Variants of Uncertain Significance in BRCA2

Overview

Journal Hum Mutat

Specialty Genetics

Date 2013 Dec 11

PMID 24323938

Citations 69

Authors

Lucia Guidugli

Aura Carreira

Sandrine M Caputo

Asa Ehlen

Alvaro Galli

Alvaro N A Monteiro

Susan L Neuhausen

Thomas V O Hansen

Fergus J Couch

Maaike P G Vreeswijk

Affiliations

Soon will be listed here.

Abstract

Missense variants in the BRCA2 gene are routinely detected during clinical screening for pathogenic mutations in patients with a family history of breast and ovarian cancer. These subtle changes frequently remain of unknown clinical significance because of the lack of genetic information that may help establish a direct correlation with cancer predisposition. Therefore, alternative ways of predicting the pathogenicity of these variants are urgently needed. Since BRCA2 is a protein involved in important cellular mechanisms such as DNA repair, replication, and cell cycle control, functional assays have been developed that exploit these cellular activities to explore the impact of the variants on protein function. In this review, we summarize assays developed and currently utilized for studying missense variants in BRCA2. We specifically depict details of each assay, including variants of uncertain significance analyzed, and describe a validation set of (genetically) proven pathogenic and neutral missense variants to serve as a golden standard for the validation of each assay. Guidelines are proposed to enable implementation of laboratory-based methods to assess the impact of the variant on cancer risk.

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