ArticleGenetics in medicine : official journal of the American College of Medical Genetics2020
Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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39 citing papers in PubMed, 58 citations in OpenAlex.
- Genomic Determinants of Lethality and Therapeutic Vulnerability in Castration-Resistant Prostate Cancer.bioRxiv : the preprint server for biology · 2026Article
- BRCA1/2 Reversion Mutations in Japanese Patients with Metastatic Breast Cancer Progressing on Olaparib: OLIVE (WJOG15321B).Breast cancer (Tokyo, Japan) · 2026Observational
- A comparative study of molecular characteristics of pathogenic and uncertain significance variants of BRCA1/2 in Chinese breast cancer patients.BMC research notes · 2026Article
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- ComprehensiveFrontiers in cell and developmental biology · 2026Article
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- Pathological features of BRCA-mutated breast cancer in Shenzhen, China: a single-center study.PeerJ · 2026Article
- Comparative genomic analysis of multiple mammary tumors from a single dog: whole-genome sequencing study.Irish veterinary journal · 2025Article
- Characterization and functional analysis of BRCA1 and BRCA2 variants in a cohort of 100 unselected patients undergoing germline screening.Translational oncology · 2025Article
- A random forest-based predictive model for classifying BRCA1 missense variants: a novel approach for evaluating the missense mutations effect.Journal of human genetics · 2025Article
- Comprehensive bioinformatics analysis of selected germline variants of uncertain significance identified in a cohort of Sri Lankan hereditary breast cancer patients.Human genomics · 2025Article
- BRCA promoter methylation in triple-negative breast cancer is preserved in xenograft models and represents a potential therapeutic marker for PARP inhibitors.Breast cancer research and treatment · 2025Article
- Article
- Reclassification of VUS inGenetics in medicine open · 2025Article
- Analysis of BRCA1 germline variants (exons 5, 11 and 20) in breast cancer families from Libya.The Libyan journal of medicine · 2024Article
- Germline Variant Spectrum in Southern Italian High-Risk Hereditary Breast Cancer Patients: Insights from Multi-Gene Panel Testing.Current issues in molecular biology · 2024Article
- Functional Characterization of the Human BRCA1 ∆11 Splicing Isoforms in Yeast.International journal of molecular sciences · 2024Article
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- Assessing the Impact of NovelCells · 2024Article
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7 authors at 3 institutions in 1 country.
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Abstract
purposeGuidelines for variant interpretation incorporate variant hotspots in critical functional domains as evidence for pathogenicity (e.g., PM1 and PP2), but do not use "coldspots," that is, regions without essential functions that tolerate variation, as evidence a variant is benign. To improve variant classification we evaluated BRCA1 and BRCA2 missense variants reported in ClinVar to identify regions where pathogenic missenses are extremely infrequent, defined as coldspots.
methodsWe used Bayesian approaches to model variant classification in these regions.
resultsBRCA1 exon 11 (~60% of the coding sequence), and BRCA2 exons 10 and 11 (~65% of the coding sequence), are coldspots. Of 89 pathogenic (P) or likely pathogenic (LP) missense variants in BRCA1, none are in exon 11 (odds <0.01, 95% confidence interval [CI] 0.0-0.01). Of 34 P or LP missense variants in BRCA2, none are in exons 10-11 (odds <0.01, 95% CI 0.0-0.01). More than half of reported missense variants of uncertain significance (VUS) in BRCA1 and BRCA2 are in coldspots (3115/5301 = 58.8%). Reclassifying these 3115 VUS as likely benign would substantially improve variant classification.
conclusionIn BRCA1 and BRCA2 coldspots, missense variants are very unlikely to be pathogenic. Classification schemes that incorporate coldspots can reduce the number of VUS and mitigate risks from reporting benign variation as VUS.
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