ArticleHuman mutation2011
Splicing and multifactorial analysis of intronic BRCA1 and BRCA2 sequence variants identifies clinically significant splicing aberrations up to 12 nucleotides from the intron/exon boundary.
Article in Human mutation, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 51 citations in OpenAlex.
- Cis-regulatory and long noncoding RNA alterations in breast cancer - current insights, biomarker utility, and the critical need for functional validation.Molecular oncology · 2026Review
- Generation of functional noncanonical donor splice sites by +2T variants in breast cancer susceptibility genes: impact on clinical interpretation.The Journal of pathology · 2026Article
- Case Report: Functional validation of a rare variantFrontiers in oncology · 2025Article
- Review
- Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.Human mutation · 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
- BRCA1-No Matter How You Splice It.Cancer research · 2019Review
- Article
- Comprehensive Assessment ofFrontiers 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
- Hereditary breast and ovarian cancer in Andalusian families: a genetic population study.BMC cancer · 2018Article
- A comparison of cosegregation analysis methods for the clinical setting.Familial cancer · 2018Article
- Splice variants of the endonucleases XPF and XPG contain residual DNA repair capabilities and could be a valuable tool for personalized medicine.Oncotarget · 2018Article
- Identification of Eight Spliceogenic Variants in BRCA2 Exon 16 by Minigene Assays.Frontiers in genetics · 2018Article
- Investigation of Experimental Factors That UnderlieFrontiers in oncology · 2018Article
- Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants.Human mutation · 2016Article
- Functional classification of BRCA2 DNA variants by splicing assays in a large minigene with 9 exons.Human mutation · 2015Article
- Editorial: BRCA1 and BRCA2 gene mutations screening in sporadic breast cancer patients in Kazakhstan.Central Asian journal of global health · 2013Article
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- Article
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Authors and funding
13 authors at 7 institutions in 2 countries.
Funding
Abstract
Clinical management of breast cancer families is complicated by identification of BRCA1 and BRCA2 sequence alterations of unknown significance. Molecular assays evaluating the effect of intronic variants on native splicing can help determine their clinical relevance. Twenty-six intronic BRCA1/2 variants ranging from the consensus dinucleotides in the splice acceptor or donor to 53 nucleotides into the intron were identified in multiple-case families. The effect of the variants on splicing was assessed using HSF matrices, MaxEntScan and NNsplice, followed by analysis of mRNA from lymphoblastoid cell lines. A total of 12 variants were associated with splicing aberrations predicted to result in production of truncated proteins, including a variant located 12 nucleotides into the intron. The posterior probability of pathogenicity was estimated using a multifactorial likelihood approach, and provided a pathogenic or likely pathogenic classification for seven of the 12 spliceogenic variants. The apparent disparity between experimental evidence and the multifactorial predictions is likely due to several factors, including a paucity of likelihood information and a nonspecific prior probability applied for intronic variants outside the consensus dinucleotides. Development of prior probabilities of pathogenicity incorporating bioinformatic prediction of splicing aberrations should improve identification of functionally relevant variants and enhance multifactorial likelihood analysis of intronic variants.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.