ArticleGenetics in medicine : official journal of the American College of Medical Genetics2019
A functional assay-based procedure to classify mismatch repair gene variants in Lynch syndrome.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38 citing papers in PubMed, 54 citations in OpenAlex.
- Characterisation of a Portuguese origin founder missense variant in MSH6.European journal of human genetics : EJHG · 2026Article
- Analysis of structure and conservation for supporting functional evaluation of PMS2 missense variants.European journal of human genetics : EJHG · 2026Article
- Validation structures for sequence variants of uncertain significance in hereditary cancer.European journal of human genetics : EJHG · 2026Review
- The Tyrolean FounderBiomolecules · 2026Article
- Lynch Syndrome: An Update of Underlying Molecular Mechanisms, Phenotypes and Methods to Classify Variants of Uncertain Significance.Biomedicines · 2026Review
- Review
- Interactions between rare variants in DNA repair genes and cardiometabolic risk explain more variability in cognitive function.GeroScience · 2026Article
- Association for Clinical Genomic Science (ACGS) guidelines for the classification of oncogenicity of somatic variants in cancer: recommendations by the UK somatic variant interpretation group (SVIG-UK).Journal of medical genetics · 2026Article
- An accurate cellular assay to determine pathogenicity of coding and noncoding variants in Lynch syndrome genes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Bayesian Integration of Tumor Mutational Signatures and Somatic Features Refines Pathogenicity Assessment of Germline Mismatch Repair Variants.Human mutation · 2026Article
- A series of reviews in familial cancer: genetic cancer risk in context variants of uncertain significance in MMR genes: which procedures should be followed?Familial cancer · 2025Review
- Disentangling the mutational effects on protein stability and interaction of human MLH1.PLoS genetics · 2025Article
- Article
- A Cell-Based Functional Assay Calibrated for Analysis ofHuman mutation · 2025Article
- Multi-dimensional Insight into the Coexistence of Pathogenic Genes for ADAR1 and TSC2: Careful Consideration is Essential for Interpretation of ADAR1 Variants.Biochemical genetics · 2024Article
- Article
- Tumor-independent Detection of Inherited Mismatch Repair Deficiency for the Diagnosis of Lynch Syndrome with High Specificity and Sensitivity.Cancer research communications · 2023Article
- Unexpected moves: a conformational change in MutSα enables high-affinity DNA mismatch binding.Nucleic acids research · 2023Article
- Constitutional mismatch repair deficiency syndrome with atypical features caused by a homozygousFrontiers in oncology · 2023Article
- A calibrated cell-based functional assay to aid classification of MLH1 DNA mismatch repair gene variants.Human mutation · 2022Article
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Authors and funding
22 authors at 7 institutions in 4 countries.
Funding
Abstract
purposeTo enhance classification of variants of uncertain significance (VUS) in the DNA mismatch repair (MMR) genes in the cancer predisposition Lynch syndrome, we developed the cell-free in vitro MMR activity (CIMRA) assay. Here, we calibrate and validate the assay, enabling its integration with in silico and clinical data.
methodsTwo sets of previously classified MLH1 and MSH2 variants were selected from a curated MMR gene database, and their biochemical activity determined by the CIMRA assay. The assay was calibrated by regression analysis followed by symmetric cross-validation and Bayesian integration with in silico predictions of pathogenicity. CIMRA assay reproducibility was assessed in four laboratories.
resultsConcordance between the training runs met our prespecified validation criterion. The CIMRA assay alone correctly classified 65% of variants, with only 3% discordant classification. Bayesian integration with in silico predictions of pathogenicity increased the proportion of correctly classified variants to 87%, without changing the discordance rate. Interlaboratory results were highly reproducible.
conclusionThe CIMRA assay accurately predicts pathogenic and benign MMR gene variants. Quantitative combination of assay results with in silico analysis correctly classified the majority of variants. Using this calibration, CIMRA assay results can be integrated into the diagnostic algorithm for MMR gene variants.
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