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Functional Assays for Analysis of Variants of Uncertain Significance in BRCA 2
Author(s) -
Guidugli Lucia,
Carreira Aura,
Caputo Sandrine M.,
Ehlen Asa,
Galli Alvaro,
Monteiro Alvaro N.A.,
Neuhausen Susan L.,
Hansen Thomas V.O.,
Couch Fergus J.,
Vreeswijk Maaike P.G.
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22478
Subject(s) - missense mutation , biology , computational biology , genetics , clinical significance , ovarian cancer , gene , mutation , breast cancer , cancer , bioinformatics , medicine
Missense variants in the BRCA 2 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 BRCA 2 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 BRCA 2 . 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.