ArticlePLoS genetics2017
Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity.
Article in PLoS genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 24 citations in OpenAlex.
- [General anatomic and histopathological diagnostic aspects of hereditary tumor syndromes : The role of pathology].Pathologie (Heidelberg, Germany) · 2026Review
- Lynch Syndrome: An Update of Underlying Molecular Mechanisms, Phenotypes and Methods to Classify Variants of Uncertain Significance.Biomedicines · 2026Review
- Genetic landscape of Chinese colorectal cancer: insights into germline and somatic mutations.BMC cancer · 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
- Lynch syndrome, molecular mechanisms and variant classification.British journal of cancer · 2023Review
- Classification of MSH6 Variants of Uncertain Significance Using Functional Assays.International journal of molecular sciences · 2021Review
- Multiplexing mutation rate assessment: determining pathogenicity of Msh2 variants in Saccharomyces cerevisiae.Genetics · 2021Article
- Quantitative evaluation of MSI testing using NGS detects the imperceptible microsatellite changed caused by MSH6 deficiency.Familial cancer · 2021Article
- Germline mutational profile of Chinese patients under 70 years old with colorectal cancer.Cancer communications (London, England) · 2020Article
- Extensive trimming of short single-stranded DNA oligonucleotides during replication-coupled gene editing in mammalian cells.PLoS genetics · 2020Article
- Stratification of patients with colorectal cancer without the recorded family history.Oncology letters · 2019Article
- Adrenal Cortical Carcinoma Associated With Lynch Syndrome: A Case Report and Review of Literature.Journal of the Endocrine Society · 2019Article
- Frequency of Mismatch Repair Protein Deficiency in a Puerto Rican Population with Colonic Adenoma and Adenocarcinoma.Cancer genomics & proteomicsArticle
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Lynch syndrome (LS) is a hereditary cancer predisposition caused by inactivating mutations in DNA mismatch repair (MMR) genes. Mutations in the MSH6 DNA MMR gene account for approximately 18% of LS cases. Many LS-associated sequence variants are nonsense and frameshift mutations that clearly abrogate MMR activity. However, missense mutations whose functional implications are unclear are also frequently seen in suspected-LS patients. To conclusively diagnose LS and enroll patients in appropriate surveillance programs to reduce morbidity as well as mortality, the functional consequences of these variants of uncertain clinical significance (VUS) must be defined. We present an oligonucleotide-directed mutagenesis screen for the identification of pathogenic MSH6 VUS. In the screen, the MSH6 variant of interest is introduced into mouse embryonic stem cells by site-directed mutagenesis. Subsequent selection for MMR-deficient cells using the DNA damaging agent 6-thioguanine (6TG) allows the identification of MMR abrogating VUS because solely MMR-deficient cells survive 6TG exposure. We demonstrate the efficacy of the genetic screen, investigate the phenotype of 26 MSH6 VUS and compare our screening results to clinical data from suspected-LS patients carrying these variant alleles.
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