A guide for functional analysis of BRCA1 variants of uncertain significance

Gaël A. Millot, Marcelo A. Carvalho, Sandrine M. Caputo, Maaike P.G. Vreeswijk, Melissa A. Brown, Michelle Webb, Etienne Rouleau, Susan L. Neuhausen, Thomas V.O. Hansen, Alvaro Galli, Rita D. Brandão, Marinus J. Blok, Aneliya Velkova, Fergus J. Couch, Alvaro N.A. Monteiro

Research output: Contribution to journalReview articlepeer-review

86 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1526-1537
Number of pages12
JournalHuman mutation
Issue number11
StatePublished - Nov 2012


  • BRCA1
  • Breast
  • Cancer
  • Functional analysis
  • Genetic testing
  • Ovarian
  • VUS

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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