ArticleCancer research2013
A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity.
Article in Cancer research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed.
- Functional characterization of BRCA2 variants of uncertain significance identified in Korean breast cancer patients.Breast cancer (Tokyo, Japan) · 2026Article
- Patient-derived organoids across cancers reveal conserved tumor heterogeneity and actionable therapeutic vulnerabilities.Science advances · 2026Article
- Systematic functional evaluation of CNGA1 missense variants associated with retinitis pigmentosa.Molecular medicine (Cambridge, Mass.) · 2026Article
- DSS1 restrains BRCA2's engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis.Nature communications · 2024Article
- The BRCA2 R2645G variant increases DNA binding and induces hyper-recombination.Nucleic acids research · 2024Article
- Digenic Inheritance of Mutations in Homologous Recombination Genes in Cancer Patients.Journal of personalized medicine · 2024Article
- The Molecular Detection of Germline Mutations in theCurrent issues in molecular biology · 2024Article
- Functional analysis and clinical classification of 462 germline BRCA2 missense variants affecting the DNA binding domain.American journal of human genetics · 2024Article
- Clinical outcomes and response to chemotherapy in a cohort of pancreatic cancer patients with germline variants of unknown significance (VUS) in BRCA1 and BRCA2 genes.Cancer chemotherapy and pharmacology · 2023Article
- Characterization of BRCA2 R3052Q variant in mice supports its functional impact as a low-risk variant.Cell death & disease · 2023Article
- The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition.Cancer science · 2023Article
- Genomics of Breast Cancer Brain Metastases: A Meta-Analysis and Therapeutic Implications.Cancers · 2023Article
- Replication gap suppression depends on the double-strand DNA binding activity of BRCA2.Nature communications · 2023Article
- Article
- Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
- Computational Biology of BRCA2 in Male Breast Cancer, through Prediction of Probable nsSNPs, and Hit Identification.ACS omega · 2022Article
- CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival.Cancers · 2022Article
- The Pathogenic R3052W BRCA2 Variant Disrupts Homology-Directed Repair by Failing to Localize to the Nucleus.Frontiers in genetics · 2022Article
- Review
- A Validated Functional Analysis of Partner and Localizer of BRCA2 Missense Variants for Use in Clinical Variant Interpretation.The Journal of molecular diagnostics : JMD · 2021Article
14 more citing papers are in PubMed but not listed here.
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15 authors.
Funding
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.
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