ArticleAmerican journal of human genetics2004
Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2.
Article in American journal of human genetics, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 181 papers.
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Who cites it
181 citing papers in PubMed.
- Finding novel vulnerabilities of hypomorphic BRCA1 alleles.Molecular oncology · 2026Article
- Combining multiplexed assays of variant effect for enhanced BRCA2 variant classification.Nature communications · 2026Article
- Integration of protein stability and AlphaMissense scores improves bioinformatic impact prediction for p53 missense and in-frame amino acid deletion variants.American journal of human genetics · 2025Article
- Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.American journal of human genetics · 2024Article
- Untapped Potential of Poly(ADP-Ribose) Polymerase Inhibitors: Lessons Learned From the Real-World Clinical Homologous Recombination Repair Mutation Testing.World journal of oncology · 2024Article
- Atypical cancer risk profile in carriers of Italian founder BRCA1 variant p.His1673del: Implications for classification and clinical management.Cancer medicine · 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
- Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2.British journal of cancer · 2023Article
- A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: application toHuman mutation · 2023Article
- Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach.Human mutation · 2022Article
- Reclassification of Five BRCA1/2 Variants with Unknown Significance Using Complex Functional Study.Cancer research and treatment · 2022Article
- An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significance.NPJ genomic medicine · 2022Article
- Comprehensive evaluation and efficient classification of BRCA1 RING domain missense substitutions.American journal of human genetics · 2022Article
- How does re-classification of variants of unknown significance (VUS) impact the management of patients at risk for hereditary breast cancer?BMC medical genomics · 2022Article
- Breast cancer risks associated with missense variants in breast cancer susceptibility genes.Genome medicine · 2022Article
- Value of the loss of heterozygosity to BRCA1 variant classification.NPJ breast cancer · 2022Article
- Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
- Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach.American journal of human genetics · 2021Article
121 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors.
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Abstract
Many sequence variants in predisposition genes are of uncertain clinical significance, and classification of these variants into high- or low-risk categories is an important problem in clinical genetics. Classification of such variants can be performed by direct epidemiological observations, including cosegregation with disease in families and degree of family history of the disease, or by indirect measures, including amino acid conservation, severity of amino acid change, and evidence from functional assays. In this study, we have developed an approach to the synthesis of such evidence in a multifactorial likelihood-ratio model. We applied this model to the analysis of three unclassified variants in BRCA1 and three in BRCA2. The evidence strongly suggests that two variants (C1787S in BRCA1 and D2723H in BRCA2) are deleterious, three (R841W in BRCA1 and Y42C and P655R in BRCA2) are neutral, and one (R1699Q in BRCA1) remains of uncertain significance. These results provide a demonstration of the utility of the model.
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