Functional Assays for Analysis of Variants of Uncertain Significance in BRCA2 |
| |
| Authors: | Asa Ehlen Alvaro Galli Alvaro N.A. Monteiro Susan L. Neuhausen Thomas V.O. Hansen |
| |
| Affiliation: | 1. Institut Curie, Research Center, Centre Universitaire, Orsay, France;2. CNRS UMR3348, Genotoxic Stress and Cancer, Orsay, France;3. Laboratorio di Terapia Genica e Molecolare Istituto di Fisiologia Clinica, CNR Area della Ricerca CNR, Pisa, Italy;4. Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, Florida;5. Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California;6. Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark |
| |
| 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. |
| |
| Keywords: | variants of uncertain significance VUS BRCA2 genetic testing functional analysis breast cancer ovarian cancer |
|
|
