ArticleAmerican journal of human genetics2007
A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes.
Article in American journal of human genetics, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 239 papers, 1 of them a synthesis that pooled it.
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Who cites it
239 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Ferroportin disease: a systematic meta-analysis of clinical and molecular findings.Journal of hepatology · 2010Pooled it
- Homologous recombination deficiency-driven genomic instability in ovarian cancer as an indicator of BRCA1 and BRCA2 variant pathogenicity.American journal of human genetics · 2026Article
- Combining multiplexed assays of variant effect for enhanced BRCA2 variant classification.Nature communications · 2026Article
- The Performance ofHuman mutation · 2026Article
- Availability of benign missense variant "truthsets" for validation of functional assays: Current status and a systematic approach.American journal of human genetics · 2025Article
- When two plus four does not equal six: Combining computational and functional evidence to classify BRCA1 key domain missense substitutions.American journal of human genetics · 2025Article
- The Time Lag Associated With the Reclassification of Germline BRCA Variants' Pathogenicity Is Critical for Cancer Patients.Cancer science · 2025Article
- Identification of Fowler syndrome (hydrocephaly-hydranencephaly proliferative vasculopathy) in a pregnancy following single euploid embryo transfer.Journal of assisted reproduction and genetics · 2025Article
- [Pathogenic large duplication in TP53 as a hereditary predisposing factor in breast cancer].Magyar onkologia · 2025Article
- Rare genetic associations with human lifespan in UK Biobank are enriched for oncogenic genes.Nature communications · 2025Article
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- Proline variants in the BRCA1 coiled-coil domain disrupt folding and binding to PALB2.Protein science : a publication of the Protein Society · 2025Article
- Reinterpretation of Conflicting ClinVarDiagnostics (Basel, Switzerland) · 2024Article
- Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.American journal of human genetics · 2024Article
- Assessment ofJCO clinical cancer informatics · 2024Article
- Challenges and approaches to calibrating patient phenotype as evidence for cancer gene variant classification under ACMG/AMP guidelines.Human molecular genetics · 2024Article
- BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer.Cancer medicine · 2024Article
- Rosetta Energy Analysis of AlphaFold2 models: Point Mutations and Conformational Ensembles.bioRxiv : the preprint server for biology · 2024Article
- Sequencing-based functional assays for classification of BRCA2 variants in mouse ESCs.Cell reports methods · 2023Article
179 more citing papers are in PubMed but not listed here.
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11 authors.
Funding
Abstract
Mutation screening of the breast and ovarian cancer-predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare nontruncating sequence variants in these genes is problematic, because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. Using data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests, we assessed the clinical significance of 1,433 sequence variants of unknown significance (VUSs) in the BRCA genes. Three independent measures were employed in the assessment: co-occurrence in trans of a VUS with known deleterious mutations; detailed analysis, by logistic regression, of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an analysis of cosegregation with disease in pedigrees. For each of these factors, a likelihood ratio was computed under the hypothesis that the VUSs were equivalent to an "average" deleterious mutation, compared with neutral, with respect to risk. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS. A total of 133 VUSs had odds of at least 100 : 1 in favor of neutrality with respect to risk, whereas 43 had odds of at least 20 : 1 in favor of being deleterious. VUSs with evidence in favor of causality were those that were predicted to affect splicing, fell at positions that are highly conserved among BRCA orthologs, and were more likely to be located in specific domains of the proteins. In addition to their utility for improved genetics counseling of patients and their families, the global assessment reported here will be invaluable for validation of functional assays, structural models, and in silico analyses.
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