ArticlePloS one2012
Analysis of 30 putative BRCA1 splicing mutations in hereditary breast and ovarian cancer families identifies exonic splice site mutations that escape in silico prediction.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 51 citations in OpenAlex.
- The emergence of Fanconi anaemia type S: a phenotypic spectrum of biallelicFrontiers in oncology · 2023Review
- Synonymous Variants: Necessary Nuance in Our Understanding of Cancer Drivers and Treatment Outcomes.Journal of the National Cancer Institute · 2022Review
- Case Review: Whole-Exome Sequencing Analyses Identify Carriers of a Known Likely Pathogenic IntronicGenes · 2022Article
- A comprehensive reference for BRCA1/2 genes pathogenic variants in Iran: published, unpublished and novel.Familial cancer · 2022Article
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- A novel frequent BRCA1 recurrent variant c.5117G > A (p.Gly1206Glu) identified after 20 years of BRCA1/2 research in the Baltic region: cohort study and literature review.Hereditary cancer in clinical practice · 2021Article
- Case Report: Prenatal Whole-Exome Sequencing to Identify a Novel Heterozygous Synonymous Variant in NIPBL in a Fetus With Cornelia de Lange Syndrome.Frontiers in genetics · 2021Article
- Unique roles of rare variants in the genetics of complex diseases in humans.Journal of human genetics · 2021Review
- Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".Genetics in medicine : official journal of the American College of Medical Genetics · 2020Article
- Somatic mRNA Analysis of BRCA1 Splice Variants Provides a Direct Theranostic Impact on PARP Inhibitors.Molecular diagnosis & therapy · 2020Article
- TheGenes · 2019Article
- Diagnostic mRNA splicing assay for variants inHereditary cancer in clinical practice · 2019Article
- Hereditary cancer genes are highly susceptible to splicing mutations.PLoS genetics · 2018Article
- No Evidence for the Pathogenicity of the BRCA2 c.6937 + 594T>G Deep Intronic Variant: A Case-Control Analysis.Genetic testing and molecular biomarkers · 2018Article
- Classification of the spliceogenicClinical case reports · 2017Article
- Nevoid basal cell carcinoma syndrome caused by splicing mutations in the PTCH1 gene.Familial cancer · 2017Article
- Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants.Human mutation · 2016Article
- Evaluation of Bioinformatic Programmes for the Analysis of Variants within Splice Site Consensus Regions.Advances in bioinformatics · 2016Article
- Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic.Breast cancer research and treatment · 2015Article
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Screening for pathogenic mutations in breast and ovarian cancer genes such as BRCA1/2, CHEK2 and RAD51C is common practice for individuals from high-risk families. However, test results may be ambiguous due to the presence of unclassified variants (UCV) in the concurrent absence of clearly cancer-predisposing mutations. Especially the presence of intronic or exonic variants within these genes that possibly affect proper pre-mRNA processing poses a challenge as their functional implications are not immediately apparent. Therefore, it appears necessary to characterize potential splicing UCV and to develop appropriate classification tools. We investigated 30 distinct BRCA1 variants, both intronic and exonic, regarding their spliceogenic potential by commonly used in silico prediction algorithms (HSF, MaxEntScan) along with in vitro transcript analyses. A total of 25 variants were identified spliceogenic, either causing/enhancing exon skipping or activation of cryptic splice sites, or both. Except from a single intronic variant causing minor effects on BRCA1 pre-mRNA processing in our analyses, 23 out of 24 intronic variants were correctly predicted by MaxEntScan, while HSF was less accurate in this cohort. Among the 6 exonic variants analyzed, 4 severely impair correct pre-mRNA processing, while the remaining two have partial effects. In contrast to the intronic alterations investigated, only half of the spliceogenic exonic variants were correctly predicted by HSF and/or MaxEntScan. These data support the idea that exonic splicing mutations are commonly disease-causing and concurrently prone to escape in silico prediction, hence necessitating experimental in vitro splicing analysis.
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