Functional assays for analysis of variants of uncertain significance in BRCA2

Lucia Guidugli, Aura Carreira, Sandrine M. Caputo, Asa Ehlen, Alvaro Galli, Alvaro N.A. Monteiro, Susan L. Neuhausen, Thomas V.O. Hansen, Fergus J. Couch, Maaike P.G. Vreeswijk

Research output: Contribution to journalReview articlepeer-review

54 Scopus citations

Abstract

Missense variants in the BRCA2 gene are routinely detected during clinical screening for pathogenic mutations in patients with a family history of breast and ovarian cancer. These subtle changes frequently remain of unknown clinical significance because of the lack of genetic information that may help establish a direct correlation with cancer predisposition. Therefore, alternative ways of predicting the pathogenicity of these variants are urgently needed. Since BRCA2 is a protein involved in important cellular mechanisms such as DNA repair, replication, and cell cycle control, functional assays have been developed that exploit these cellular activities to explore the impact of the variants on protein function. In this review, we summarize assays developed and currently utilized for studying missense variants in BRCA2. We specifically depict details of each assay, including variants of uncertain significance analyzed, and describe a validation set of (genetically) proven pathogenic and neutral missense variants to serve as a golden standard for the validation of each assay. Guidelines are proposed to enable implementation of laboratory-based methods to assess the impact of the variant on cancer risk.

Original languageEnglish (US)
Pages (from-to)151-164
Number of pages14
JournalHuman mutation
Volume35
Issue number2
DOIs
StatePublished - Feb 2014

Keywords

  • BRCA2
  • Breast cancer
  • Functional analysis
  • Genetic testing
  • Ovarian cancer
  • VUS
  • Variants of uncertain significance

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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