A Classification Model for BRCA2 DNA Binding Domain Missense Variants Based on Homology-Directed Repair Activity
Open Access
- 1 January 2013
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 73 (1), 265-275
- https://doi.org/10.1158/0008-5472.can-12-2081
Abstract
The relevance of many BRCA2 variants of uncertain significance (VUS) to breast cancer has not been determined due to limited genetic information from families carrying these alterations. Here, we classified six new variants as pathogenic or nonpathogenic by analysis of genetic information from families carrying 64 individual BRCA2 DNA binding domain (DBD) missense mutations using a multifactorial likelihood model of cancer causality. Next, we evaluated the use of a homology-directed DNA break repair (HDR) functional assay as a method for inferring the clinical relevance of VUS in the DBD of BRCA2 using 18 established nonpathogenic missense variants and all 13 established pathogenic missense mutations from the BRCA2 DBD. Compared with the known status of these variants based on the multifactorial likelihood model, the sensitivity of the HDR assay for pathogenic mutations was estimated at 100% [95% confidence interval (CI): 75.3%–100%] and specificity was estimated at 100% (95% CI: 81.5%–100%). A statistical classifier for predicting the probability of pathogenicity of BRCA2 DBD variants was developed using these functional results. When applied to 33 additional VUS, the classifier identified eight with 99% or more probability of nonpathogenicity and 18 with 99% or more probability of pathogenicity. Thus, in the absence of genetic evidence, a cell-based HDR assay can provide a probability of pathogenicity for all VUS in the BRCA2 DBD, suggesting that the assay can be used in combination with other information to determine the cancer relevance of BRCA2 VUS. Cancer Res; 73(1); 265–75. ©2012 AACR.Keywords
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This publication has 29 references indexed in Scilit:
- Classification of missense substitutions in the BRCA genes: A database dedicated to Ex-UVsHuman Mutation, 2011
- ENIGMA-Evidence-based network for the interpretation of germline mutant alleles: An international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genesHuman Mutation, 2011
- A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS)Human Mutation, 2011
- Purified human BRCA2 stimulates RAD51-mediated recombinationNature, 2010
- Detection of splicing aberrations caused by BRCA1 and BRCA2 sequence variants encoding missense substitutions: implications for prediction of pathogenicityHuman Mutation, 2010
- Assessment of functional effects of unclassified genetic variantsHuman Mutation, 2008
- In silico analysis of missense substitutions using sequence-alignment based methodsHuman Mutation, 2008
- Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test resultsHuman Mutation, 2008
- The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensionsBritish Journal of Cancer, 2008
- Maximum Entropy Modeling of Short Sequence Motifs with Applications to RNA Splicing SignalsJournal of Computational Biology, 2004