A Guide for Functional Analysis of BRCA1 Variants of Uncertain Significance (VUS)
By G. Millot, Marcelo A. Carvalho, Sandrine M Caputo, M. Vreeswijk, Melissa A. Brown, M. Webb, E. Rouleau, S. Neuhausen, T. Hansen, A. Galli and 5 more. 2012
132 citations recorded by the source corpus.
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.
Subfields: Genetics, Molecular Biology
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Citations in the corpus
- Analysis of BRCA1 Variants in Double-Strand Break Repair by Homologous Recombination and Single-Strand Annealing (2012, background): “These approaches have been successful in reclassification of variants but are also incomplete because they cannot definitively determine whether any given variant affects the critical cancer suppressing function(s) of the protein [Millot et al., 2012].”