ArticleHuman mutation2019
Functional interrogation of Lynch syndrome-associated MSH2 missense variants via CRISPR-Cas9 gene editing in human embryonic stem cells.
Article in Human mutation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 34 citations in OpenAlex.
- Lynch Syndrome: An Update of Underlying Molecular Mechanisms, Phenotypes and Methods to Classify Variants of Uncertain Significance.Biomedicines · 2026Review
- 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
- Editing stem cell genomes at scale to measure variant effects in diverse cell and genetic contexts.medRxiv : the preprint server for health sciences · 2025Article
- Genome-Wide Screening in Haploid Stem Cells Reveals Synthetic Lethality Targeting MLH1 and TP53 Deficient Tumours.Cell proliferation · 2025Article
- A Cell-Based Functional Assay Calibrated for Analysis ofHuman mutation · 2025Article
- Functional and phenotypic consequences of an unusual inversion in MSH2.Familial cancer · 2024Article
- CRISPR/Cas9: a powerful tool in colorectal cancer research.Journal of experimental & clinical cancer research : CR · 2023Review
- Whole exome sequencing identifies MAP3K1, MSH2, and MLH1 as potential cancer-predisposing genes in familial early-onset colorectal cancer.The Kaohsiung journal of medical sciences · 2023Article
- CRaTER enrichment for on-target gene editing enables generation of variant libraries in hiPSCs.Journal of molecular and cellular cardiology · 2023Article
- Application of CRISPR-Cas9 gene editing technology in basic research, diagnosis and treatment of colon cancer.Frontiers in endocrinology · 2023Review
- Loss of mismatch repair promotes a direct selective advantage in human stem cells.Stem cell reports · 2022Article
- A calibrated cell-based functional assay to aid classification of MLH1 DNA mismatch repair gene variants.Human mutation · 2022Article
- Predictive functional assay-based classification of PMS2 variants in Lynch syndrome.Human mutation · 2022Article
- Multiplexing mutation rate assessment: determining pathogenicity of Msh2 variants in Saccharomyces cerevisiae.Genetics · 2021Article
- Review
- Article
- Integrative identification of the pathogenic role of a novel G6PD missense mutation c.697G>C.Annals of translational medicine · 2021Article
- Contribution of mRNA Splicing to Mismatch Repair Gene Sequence Variant Interpretation.Frontiers in genetics · 2020Article
- New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients.Frontiers in genetics · 2020Article
- Pulmonary Artery Intimal Sarcoma in a Patient with Lynch Syndrome: Response to an Immune Checkpoint Inhibitor.Case reports in oncologyArticle
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Authors and funding
10 authors at 5 institutions in 1 country.
Funding
Abstract
Lynch syndrome (LS) predisposes patients to cancer and is caused by germline mutations in the DNA mismatch repair (MMR) genes. Identifying the deleterious mutation, such as a frameshift or nonsense mutation, is important for confirming an LS diagnosis. However, discovery of a missense variant is often inconclusive. The effects of these variants of uncertain significance (VUS) on disease pathogenesis are unclear, though understanding their impact on protein function can help determine their significance. Laboratory functional studies performed to date have been limited by their artificial nature. We report here an in-cellulo functional assay in which we engineered site-specific MSH2 VUS using clustered regularly interspaced short palindromic repeats-Cas9 gene editing in human embryonic stem cells. This approach introduces the variant into the endogenous MSH2 loci, while simultaneously eliminating the wild-type gene. We characterized the impact of the variants on cellular MMR functions including DNA damage response signaling and the repair of DNA microsatellites. We classified the MMR functional capability of eight of 10 VUS providing valuable information for determining their likelihood of being bona fide pathogenic LS variants. This human cell-based assay system for functional testing of MMR gene VUS will facilitate the identification of high-risk LS patients.
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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.