A guide for functional analysis ofBRCA1variants of uncertain significance
Year: 2012
Type: review
Abstract: 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.
Source: Human Mutation
DOI: 10.1002/humu.22150
Institutions: Centre National de la Recherche Scientifique, Dynamique de l'information génétique : bases fondamentales et cancer, Université Pierre-et-Marie-Curie, Institut Curie, Instituto Federal do Rio de Janeiro, Instituto Nacional de Câncer - INCA, Inserm, Hôpital René Huguenin, Leiden University Medical Center, The University of Queensland, University of Manchester, Beckman Research Institute, Copenhagen University Hospital, Rigshospitalet, Istituto di Fisiologia Clinica, National Research Council, Maastricht University Medical Centre, Moffitt Cancer Center, Mayo Clinic
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funder: National Cancer Institute
OpenAlex ID: W2120641928