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 journalArticle

77 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1526-1537
Number of pages12
JournalHuman Mutation
Volume33
Issue number11
DOIs
StatePublished - Nov 2012

Fingerprint

Genetic Testing
Ovarian Neoplasms
Breast Neoplasms
Protein Conformation
Preventive Medicine
Germ-Line Mutation
Tumor Suppressor Genes
Virulence
Counseling
Genome
Mutation
Proteins

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Millot, G. A., Carvalho, M. A., Caputo, S. M., Vreeswijk, M. P. G., Brown, M. A., Webb, M., ... Monteiro, A. N. A. (2012). A guide for functional analysis of BRCA1 variants of uncertain significance. Human Mutation, 33(11), 1526-1537. https://doi.org/10.1002/humu.22150

A guide for functional analysis of BRCA1 variants of uncertain significance. / 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.

In: Human Mutation, Vol. 33, No. 11, 11.2012, p. 1526-1537.

Research output: Contribution to journalArticle

Millot, GA, Carvalho, MA, Caputo, SM, Vreeswijk, MPG, Brown, MA, Webb, M, Rouleau, E, Neuhausen, SL, Hansen, TVO, Galli, A, Brandão, RD, Blok, MJ, Velkova, A, Couch, FJ & Monteiro, ANA 2012, 'A guide for functional analysis of BRCA1 variants of uncertain significance', Human Mutation, vol. 33, no. 11, pp. 1526-1537. https://doi.org/10.1002/humu.22150
Millot GA, Carvalho MA, Caputo SM, Vreeswijk MPG, Brown MA, Webb M et al. A guide for functional analysis of BRCA1 variants of uncertain significance. Human Mutation. 2012 Nov;33(11):1526-1537. https://doi.org/10.1002/humu.22150
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. / A guide for functional analysis of BRCA1 variants of uncertain significance. In: Human Mutation. 2012 ; Vol. 33, No. 11. pp. 1526-1537.
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