ArticleHuman mutation2009
Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics.
Article in Human mutation, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
33 citing papers in PubMed.
- Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals.Journal of human genetics · 2018Trial
- pLM-SAV: a Δ-embedding approach for predicting pathogenic single amino acid variants.Bioinformatics advances · 2026Article
- Case Report: A case of Lynch syndrome-related glioblastoma with coexistingFrontiers in oncology · 2026Article
- Article
- Left-sided colorectal cancer distinct in indigenous African patients compared to other ethnic groups in South Africa.BMC cancer · 2022Article
- MLH1 Exon 12 Gene Deletion Leading to Lynch Syndrome: A Case Report.Oncology research and treatment · 2021Article
- Characterization of a germline splice site variant MLH1 c.678-3T>A in a Lynch syndrome family.Familial cancer · 2020Article
- Haplotype analysis suggest that the MLH1 c.2059C > T mutation is a Swedish founder mutation.Familial cancer · 2018Article
- A comparison of cosegregation analysis methods for the clinical setting.Familial cancer · 2018Article
- Article
- Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2017Article
- Computational analysis of the mutations in BAP1, PBRM1 and SETD2 genes reveals the impaired molecular processes in renal cell carcinoma.Oncotarget · 2015Article
- Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases.World journal of gastroenterology · 2015Article
- RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.Science (New York, N.Y.) · 2015Article
- Aberrant methylation patterns in cancer: a clinical view.Biochemia medica · 2015Review
- Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.Nature genetics · 2014Article
- Estimating risks for variants of unknown significance according to their predicted pathogenicity classes with application to BRCA1.Breast cancer research and treatment · 2014Article
- Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2014Article
- Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Review
Corrections and comments
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Authors and funding
14 authors.
Funding
Abstract
Reliable methods for predicting functional consequences of variants in disease genes would be beneficial in the clinical setting. This study was undertaken to predict, and confirm in vitro, splicing aberrations associated with mismatch repair (MMR) variants identified in familial colon cancer patients. Six programs were used to predict the effect of 13 MLH1 and 6 MSH2 gene variants on pre-mRNA splicing. mRNA from cycloheximide-treated lymphoblastoid cell lines of variant carriers was screened for splicing aberrations. Tumors of variant carriers were tested for microsatellite instability and MMR protein expression. Variant segregation in families was assessed using Bayes factor causality analysis. Amino acid alterations were examined for evolutionary conservation and physicochemical properties. Splicing aberrations were detected for 10 variants, including a frameshift as a minor cDNA product, and altered ratio of known alternate splice products. Loss of splice sites was well predicted by splice-site prediction programs SpliceSiteFinder (90%) and NNSPLICE (90%), but consequence of splice site loss was less accurately predicted. No aberrations correlated with ESE predictions for the nine exonic variants studied. Seven of eight missense variants had normal splicing (88%), but only one was a substitution considered neutral from evolutionary/physicochemical analysis. Combined with information from tumor and segregation analysis, and literature review, 16 of 19 variants were considered clinically relevant. Bioinformatic tools for prediction of splicing aberrations need improvement before use without supporting studies to assess variant pathogenicity. Classification of mismatch repair gene variants is assisted by a comprehensive approach that includes in vitro, tumor pathology, clinical, and evolutionary conservation data.
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