ArticleEuropean journal of human genetics : EJHG2011
Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes.
Article in European journal of human genetics : EJHG, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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53 citing papers in PubMed.
- 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
- VNTR Polymorphism in the Intron 5 of SIRT3 and Susceptibility to Breast Cancer.Asian Pacific journal of cancer prevention : APJCP · 2023Article
- A novelFrontiers in genetics · 2023Article
- Synonymous Variants: Necessary Nuance in Our Understanding of Cancer Drivers and Treatment Outcomes.Journal of the National Cancer Institute · 2022Review
- Analysis ofFrontiers in genetics · 2022Article
- Epidemiological and ES cell-based functional evaluation of BRCA2 variants identified in families with breast cancer.Human mutation · 2021Article
- Characterization of SynonymousFrontiers in oncology · 2021Article
- Calibration of Pathogenicity Due to Variant-Induced Leaky Splicing Defects by UsingCancer research · 2020Article
- Variation benchmark datasets: update, criteria, quality and applications.Database : the journal of biological databases and curation · 2020Article
- BRCA1 and BRCA2 mutations in a sample of breast and ovarian cancer families from the Colombian pacific.Colombia medica (Cali, Colombia) · 2019Article
- Targeted RNA-seq successfully identifies normal and pathogenic splicing events in breast/ovarian cancer susceptibility and Lynch syndrome genes.International journal of cancer · 2019Article
- Functional coding and non-coding variants in human BRCA1 gene and their use in genetic screening.Medical oncology (Northwood, London, England) · 2019Review
- A plugin for the Ensembl Variant Effect Predictor that uses MaxEntScan to predict variant spliceogenicity.Bioinformatics (Oxford, England) · 2019Article
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- Pathogenicity and selective constraint on variation near splice sites.Genome research · 2019Article
- Functional Characterization of Argininosuccinate Lyase Gene Variants by Mini-Gene Splicing Assay.Frontiers in genetics · 2019Article
- Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort.Nucleic acids research · 2018Article
- Splicing mutations in human genetic disorders: examples, detection, and confirmation.Journal of applied genetics · 2018Review
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15 authors.
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Abstract
A large fraction of sequence variants of unknown significance (VUS) of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 may induce splicing defects. We analyzed 53 VUSs of BRCA1 or BRCA2, detected in consecutive molecular screenings, by using five splicing prediction programs, and we classified them into two groups according to the strength of the predictions. In parallel, we tested them by using functional splicing assays. A total of 10 VUSs were predicted by two or more programs to induce a significant reduction of splice site strength or activation of cryptic splice sites or generation of new splice sites. Minigene-based splicing assays confirmed four of these predictions. Five additional VUSs, all at internal exon positions, were not predicted to induce alterations of splice sites, but revealed variable levels of exon skipping, most likely induced by the modification of exonic splicing regulatory elements. We provide new data in favor of the pathogenic nature of the variants BRCA1 c.212+3A>G and BRCA1 c.5194-12G>A, which induced aberrant out-of-frame mRNA forms. Moreover, the novel variant BRCA2 c.7977-7C>G induced in frame inclusion of 6 nt from the 3' end of intron 17. The novel variants BRCA2 c.520C>T and BRCA2 c.7992T>A induced incomplete skipping of exons 7 and 18, respectively. This work highlights the contribution of splicing minigene assays to the assessment of pathogenicity, not only when patient RNA is not available, but also as a tool to improve the accuracy of bioinformatics predictions.
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