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A guide for functional analysis of BRCA1 variants of uncertain significance
Author(s) -
Millot Gaël A.,
Carvalho Marcelo A.,
Caputo Sandrine M.,
Vreeswijk Maaike P.G.,
Brown Melissa A.,
Webb Michelle,
Rouleau Etienne,
Neuhausen Susan L.,
Hansen Thomas v. O.,
Galli Alvaro,
Brandão Rita D.,
Blok Marinus J.,
Velkova Aneliya,
Couch Fergus J.,
Monteiro Alvaro N.A.
Publication year - 2012
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.22150
Subject(s) - biology , germline , genetic testing , breast cancer , ovarian cancer , genetics , genetic counseling , clinical significance , gene , germline mutation , mutation , computational biology , cancer , bioinformatics , medicine
Germline mutations in the tumor suppressor gene BRCA1 confer an estimated lifetime risk of 56–80% for breast cancer and 15–60% for ovarian cancer. Since the mid 1990s when BRCA1 was identified, genetic testing has revealed over 1,500 unique germline variants. However, for a significant number of these variants, the effect on protein function is unknown making it difficult to infer the consequences on risks of breast and ovarian cancers. Thus, many individuals undergoing genetic testing for BRCA1 mutations receive test results reporting a variant of uncertain clinical significance (VUS), leading to issues in risk assessment, counseling, and preventive care. Here, we describe functional assays for BRCA1 to directly or indirectly assess the impact of a variant on protein conformation or function and how these results can be used to complement genetic data to classify a VUS as to its clinical significance. Importantly, these methods may provide a framework for genome‐wide pathogenicity assignment. Hum Mutat 33:1526–1537, 2012. © 2012 Wiley Periodicals, Inc.