ArticleAmerican journal of human genetics2018
Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes.
Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Germline pathogenic variant spectrum and prevalence among colorectal cancer patients undergoing multigene panel testing in Kazakhstan.Scientific reports · 2026Article
- Tumor analysis of MMR genes in Lynch-like syndrome: Challenges associated with results interpretation.Cancer medicine · 2024Article
- Prognostic potential of whole exome sequencing in the clinical management of metachronous colorectal cancer liver metastases.Cancer cell international · 2023Article
- Article
- A Novel Mutation ofJournal of clinical medicine · 2023Article
- Multi-omic analysis in normal colon organoids highlights MSH4 as a novel marker of defective mismatch repair in Lynch syndrome and microsatellite instability.Cancer medicine · 2023Article
- Saturation-scale functional evidence supports clinical variant interpretation in Lynch syndrome.Genome biology · 2022Article
- Synonymous Variants: Necessary Nuance in Our Understanding of Cancer Drivers and Treatment Outcomes.Journal of the National Cancer Institute · 2022Review
- Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures.Nature communications · 2022Article
- Therapeutic implications of germline vulnerabilities in DNA repair for precision oncology.Cancer treatment reviews · 2022Review
- Sporadic and Lynch syndrome-associated mismatch repair-deficient brain tumors.Laboratory investigation; a journal of technical methods and pathology · 2022Article
- Case report: Undifferentiated sarcoma with multiple tumors involved in Lynch syndrome: Unexpected favorable outcome to sintilimab combined with chemotherapy.Frontiers in oncology · 2022Article
- Alternative splicing of mRNA in colorectal cancer: new strategies for tumor diagnosis and treatment.Cell death & disease · 2021Review
- Somatic Tumor Profile Analysis in a Patient with GermlineJournal of personalized medicine · 2021Article
- Multiplexing mutation rate assessment: determining pathogenicity of Msh2 variants in Saccharomyces cerevisiae.Genetics · 2021Article
- Germline and Tumor Sequencing as a Diagnostic Tool To Resolve Suspected Lynch Syndrome.The Journal of molecular diagnostics : JMD · 2021Article
- How Should We Test for Lynch Syndrome? A Review of Current Guidelines and Future Strategies.Cancers · 2021Review
- Prospective Statewide Study of Universal Screening for Hereditary Colorectal Cancer: The Ohio Colorectal Cancer Prevention Initiative.JCO precision oncology · 2021Article
- A Novel Splice-Site Mutation inFrontiers in oncology · 2020Article
- Colorectal carcinoma with double somatic mismatch repair gene inactivation: clinical and pathological characteristics and response to immune checkpoint blockade.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2019Article
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
Present guidelines for classification of constitutional variants do not incorporate inferences from mutations seen in tumors, even when these are associated with a specific molecular phenotype. When somatic mutations and constitutional mutations lead to the same molecular phenotype, as for the mismatch repair genes, information from somatic mutations may enable interpretation of previously unclassified variants. To test this idea, we first estimated likelihoods that somatic variants in MLH1, MSH2, MSH6, and PMS2 drive microsatellite instability and characteristic IHC staining patterns by calculating likelihoods of high versus low normalized variant read fractions of 153 mutations known to be pathogenic versus those of 760 intronic passenger mutations from 174 paired tumor-normal samples. Mutations that explained the tumor mismatch repair phenotype had likelihood ratio for high variant read fraction of 1.56 (95% CI 1.42-1.71) at sites with no loss of heterozygosity and of 26.5 (95% CI 13.2-53.0) at sites with loss of heterozygosity. Next, we applied these ratios to 165 missense, synonymous, and splice variants observed in tumors, combining in a Bayesian analysis the likelihood ratio corresponding with the adjusted variant read fraction with pretest probabilities derived from published analyses and public databases. We suggest classifications for 86 of 165 variants: 7 benign, 31 likely benign, 22 likely pathogenic, and 26 pathogenic. These results illustrate that for mismatch repair genes, characterization of tumor mutations permits tumor mutation data to inform constitutional variant classification. We suggest modifications to incorporate molecular phenotype in future variant classification guidelines.
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