ArticleProceedings of the National Academy of Sciences of the United States of America2016
Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed, 35 citations in OpenAlex.
- 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
- A novel frameshift variant inFrontiers in medicine · 2026Article
- Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants.NPJ precision oncology · 2024Article
- Using metabolic abnormalities of carriers in the neonatal period to evaluate the pathogenicity of variants of uncertain significance in methylmalonic acidemia.Frontiers in genetics · 2024Article
- 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
- Lynch syndrome, molecular mechanisms and variant classification.British journal of cancer · 2023Review
- Unexpected moves: a conformational change in MutSα enables high-affinity DNA mismatch binding.Nucleic acids research · 2023Article
- Predictive functional assay-based classification of PMS2 variants in Lynch syndrome.Human mutation · 2022Article
- Multiplexed assays reveal effects of missense variants in MSH2 and cancer predisposition.PLoS genetics · 2021Article
- How Should We Test for Lynch Syndrome? A Review of Current Guidelines and Future Strategies.Cancers · 2021Review
- Extensive trimming of short single-stranded DNA oligonucleotides during replication-coupled gene editing in mammalian cells.PLoS genetics · 2020Article
- New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients.Frontiers in genetics · 2020Article
- Targeted sequencing of genes associated with the mismatch repair pathway in patients with endometrial cancer.PloS one · 2020Article
- Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases.Scientific reports · 2019Article
- Functional interrogation of Lynch syndrome-associated MSH2 missense variants via CRISPR-Cas9 gene editing in human embryonic stem cells.Human mutation · 2019Article
- Endoscopic full thickness resection for early colon cancer in Lynch syndrome.Familial cancer · 2019Article
- Article
- Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity.PLoS genetics · 2017Article
- Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations.PLoS genetics · 2017Article
- The effect of S-substitution at the O6-guanine site on the structure and dynamics of a DNA oligomer containing a G:T mismatch.PloS one · 2017Article
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8 authors at 3 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Single-stranded DNA oligonucleotides can achieve targeted base-pair substitution with modest efficiency but high precision. We show that "oligo targeting" can be used effectively to study missense mutations in DNA mismatch repair (MMR) genes. Inherited inactivating mutations in DNA MMR genes are causative for the cancer predisposition Lynch syndrome (LS). Although overtly deleterious mutations in MMR genes can clearly be ascribed as the cause of LS, the functional implications of missense mutations are often unclear. We developed a genetic screen to determine the pathogenicity of these variants of uncertain significance (VUS), focusing on mutator S homolog 2 (MSH2). VUS were introduced into the endogenous Msh2 gene of mouse embryonic stem cells by oligo targeting. Subsequent selection for MMR-deficient cells using the guanine analog 6-thioguanine allowed the detection of MMR-abrogating VUS. The screen was able to distinguish weak and strong pathogenic variants from polymorphisms and was used to investigate 59 Msh2 VUS. Nineteen of the 59 VUS were identified as pathogenic. Functional assays revealed that 14 of the 19 detected variants fully abrogated MMR activity and that five of the detected variants attenuated MMR activity. Implementation of the screen in clinical practice allows proper counseling of mutation carriers and treatment of their tumors.
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