ArticleAmerican journal of human genetics2021
Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-binding-domain variants of uncertain significance.
Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 61 citations in OpenAlex.
- Functional assays for BRCA1 and BRCA2 variant analysis: new tools and their applications.NPJ breast cancer · 2026Review
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- Equity-aware variant interpretation needs local allele frequencies and calibrated functional evidence: comment on Bianco & Planello (2025).Molecular genetics and genomics : MGG · 2026Article
- High-throughput screens identify genotype-specific therapeutics for channelopathies.JCI insight · 2025Article
- Reclassification of ATM Missense Variants of Uncertain Significance by Integrating Results from Systematic Functional Assays into an ACMG Points-Based Framework.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Prime editing outperforms homology-directed repair as a tool for CRISPR-mediated variant knock-in in zebrafish.Lab animal · 2025Article
- Article
- Article
- Expanding the phenotypic and genetic spectrum of GTPBP3 deficiency: findings from nine Chinese pedigrees.Orphanet journal of rare diseases · 2024Article
- DSS1 restrains BRCA2's engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis.Nature communications · 2024Article
- Germline Genetic Testing for Hereditary Breast and Ovarian Cancer: Current Concepts in Risk Evaluation.Cold Spring Harbor perspectives in medicine · 2024Review
- Scalable approaches for generating, validating and incorporating data from high-throughput functional assays to improve clinical variant classification.Human genetics · 2024Article
- Article
- 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
- Assessment ofJCO clinical cancer informatics · 2024Article
- Functional analysis and clinical classification of 462 germline BRCA2 missense variants affecting the DNA binding domain.American journal of human genetics · 2024Article
- Saturation genome editing of 11 codons and exon 13 of BRCA2 coupled with chemotherapeutic drug response accurately determines pathogenicity of variants.PLoS genetics · 2023Article
- Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C.Cancer research · 2023Article
- The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition.Cancer science · 2023Article
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 1 country.
Funding
Abstract
Determination of the clinical relevance of rare germline variants of uncertain significance (VUSs) in the BRCA2 cancer predisposition gene remains a challenge as a result of limited availability of data for use in classification models. However, laboratory-based functional data derived from validated functional assays of known sensitivity and specificity may influence the interpretation of VUSs. We evaluated 252 missense VUSs from the BRCA2 DNA-binding domain by using a homology-directed DNA repair (HDR) assay and identified 90 as non-functional and 162 as functional. The functional assay results were integrated with other available data sources into an ACMG/AMP rules-based classification framework used by a hereditary cancer testing laboratory. Of the 186 missense variants observed by the testing laboratory, 154 were classified as VUSs without functional data. However, after applying protein functional data, 86% (132/154) of the VUSs were reclassified as either likely pathogenic/pathogenic (39/132) or likely benign/benign (93/132), which impacted testing results for 1,900 individuals. These results indicate that validated functional assay data can have a substantial impact on VUS classification and associated clinical management for many individuals with inherited alterations in BRCA2.
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