ArticleHuman mutation2016
Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants.
Article in Human mutation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed.
- Clinical variant interpretation comparing two saturation genome editing-based functional studies forFrontiers in genetics · 2026Article
- The SeqSplice multiplexed minigene splicing assay for characterization and quantitation of variant-inducedGenome research · 2025Article
- A founder BRCA1 exonic duplication involving breakpoint in T2T reference genome-specific region results in constitutional fusion transcript.NPJ genomic medicine · 2025Article
- Meta-EA: a gene-specific combination of available computational tools for predicting missense variant effects.Nature communications · 2025Article
- Sequencing-based functional assays for classification of BRCA2 variants in mouse ESCs.Cell reports methods · 2023Article
- PDIVAS: Pathogenicity predictor for Deep-Intronic Variants causing Aberrant Splicing.BMC genomics · 2023Article
- Functional Analyses of Rare Germline MissenseGenes · 2023Article
- Comprehensive evaluation and efficient classification of BRCA1 RING domain missense substitutions.American journal of human genetics · 2022Article
- Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
- Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach.American journal of human genetics · 2021Article
- 5' Region Large Genomic Rearrangements in theCancers · 2021Article
- A Population-Based Analysis ofCancers · 2021Article
- Epidemiological and ES cell-based functional evaluation of BRCA2 variants identified in families with breast cancer.Human mutation · 2021Article
- A computational model for classification of BRCA2 variants using mouse embryonic stem cell-based functional assays.NPJ genomic medicine · 2020Article
- Review
- Impact of proactive high-throughput functional assay data on BRCA1 variant interpretation in 3684 patients with breast or ovarian cancer.Journal of human genetics · 2020Article
- Mutational Screening of BRCA1/2 Genes as a Predictive Factor for Therapeutic Response in Epithelial Ovarian Cancer: A Consensus Guide from the Spanish Society of Pathology (SEAP-IAP) and the Spanish Society of Human Genetics (AEGH).Virchows Archiv : an international journal of pathology · 2020Review
- BRCA1- and BRCA2-specific in silico tools for variant interpretation in the CAGI 5 ENIGMA challenge.Human mutation · 2019Article
- Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.Human mutation · 2019Article
- Assessment of blind predictions of the clinical significance of BRCA1 and BRCA2 variants.Human mutation · 2019Article
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11 authors.
Funding
Abstract
Clinical mutation screening of the cancer susceptibility genes BRCA1 and BRCA2 generates many unclassified variants (UVs). Most of these UVs are either rare missense substitutions or nucleotide substitutions near the splice junctions of the protein coding exons. Previously, we developed a quantitative method for evaluation of BRCA gene UVs-the "integrated evaluation"-that combines a sequence analysis-based prior probability of pathogenicity with patient and/or tumor observational data to arrive at a posterior probability of pathogenicity. One limitation of the sequence analysis-based prior has been that it evaluates UVs from the perspective of missense substitution severity but not probability to disrupt normal mRNA splicing. Here, we calibrated output from the splice-site fitness program MaxEntScan to generate spliceogenicity-based prior probabilities of pathogenicity for BRCA gene variants; these range from 0.97 for variants with high probability to damage a donor or acceptor to 0.02 for exonic variants that do not impact a splice junction and are unlikely to create a de novo donor. We created a database http://priors.hci.utah.edu/PRIORS/ that provides the combined missense substitution severity and spliceogenicity-based probability of pathogenicity for BRCA gene single-nucleotide substitutions. We also updated the BRCA gene Ex-UV LOVD, available at http://hci-exlovd.hci.utah.edu, with 77 re-evaluable variants.
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