ArticlePloS one2014
Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Comprehensive evaluation and efficient classification of BRCA1 RING domain missense substitutions.American journal of human genetics · 2022Article
- Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".Genetics in medicine : official journal of the American College of Medical Genetics · 2020Article
- Contribution of mRNA Splicing to Mismatch Repair Gene Sequence Variant Interpretation.Frontiers in genetics · 2020Article
- Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.Annals of oncology : official journal of the European Society for Medical Oncology · 2019Article
- Lessons learned from two decades of BRCA1 and BRCA2 genetic testing: the evolution of data sharing and variant classification.Genetics in medicine : official journal of the American College of Medical Genetics · 2019Review
- Article
- Performance of in silico prediction tools for the classification of rare BRCA1/2 missense variants in clinical diagnostics.BMC medical genomics · 2018Article
- Clinical Variant Classification: A Comparison of Public Databases and a Commercial Testing Laboratory.The oncologist · 2017Article
- Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants.Human mutation · 2016Article
- DNA methylation profiling to assess pathogenicity of BRCA1 unclassified variants in breast cancer.Epigenetics · 2015Article
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Authors and funding
11 authors.
Funding
Abstract
Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and/or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic (Class 5). BRCA1:c.4484G> C(p.Arg1495Thr) was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.His41Arg) RING-domain variant was found from multifactorial likelihood analysis to have a posterior probability of pathogenicity of 0.995, a result consistent with existing protein functional assay data indicating lost BARD1 binding and ubiquitin ligase activity. Of the remaining variants, seven were determined to be not clinically significant (Class 1), nine were likely not pathogenic (Class 2), and one was uncertain (Class 3).These results have implications for genetic counseling and medical management of families carrying these specific variants. They also provide additional multifactorial likelihood variant classifications as reference to evaluate the sensitivity and specificity of bioinformatic prediction tools and/or functional assay data in future studies.
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