ArticleHereditary cancer in clinical practice2012
Determining the functional significance of mismatch repair gene missense variants using biochemical and cellular assays.
Article in Hereditary cancer in clinical practice, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- 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
- A Cell-Based Functional Assay Calibrated for Analysis ofHuman mutation · 2025Article
- A calibrated cell-based functional assay to aid classification of MLH1 DNA mismatch repair gene variants.Human mutation · 2022Article
- Review
- Linker domain function predicts pathogenic MLH1 missense variants.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors.Cancers · 2021Review
- Functional interrogation of Lynch syndrome-associated MSH2 missense variants via CRISPR-Cas9 gene editing in human embryonic stem cells.Human mutation · 2019Article
- Article
- Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene.Human mutation · 2019Article
- The changing landscape of Lynch syndrome due to PMS2 mutations.Clinical genetics · 2018Review
- Functional analysis of rare variants in mismatch repair proteins augments results from computation-based predictive methods.Cancer biology & therapy · 2017Article
- Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Enhanced gene targeting to evaluate Lynch syndrome alterations.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Mismatch repair defects and Lynch syndrome: The role of the basic scientist in the battle against cancer.DNA repair · 2016Review
- Consequences of germline variation disrupting the constitutional translational initiation codon start sites of MLH1 and BRCA2: Use of potential alternative start sites and implications for predicting variant pathogenicity.Molecular carcinogenesis · 2015Article
- Milestones of Lynch syndrome: 1895-2015.Nature reviews. Cancer · 2015Review
- Genetic predisposition to colorectal cancer: where we stand and future perspectives.World journal of gastroenterology · 2014Review
- Functional implications of the p.Cys680Arg mutation in the MLH1 mismatch repair protein.Molecular genetics & genomic medicine · 2014Article
- Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.Nature genetics · 2014Article
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2 authors.
Funding
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Abstract
With the discovery that the hereditary cancer susceptibility disease Lynch syndrome (LS) is caused by deleterious germline mutations in the DNA mismatch repair (MMR) genes nearly 20 years ago, genetic testing can now be used to diagnose this disorder in patients. A definitive diagnosis of LS can direct how clinicians manage the disease as well as prevent future cancers for the patient and their families. A challenge emerges, however, when a germline missense variant is identified in a MMR gene in a suspected LS patient. The significance of a single amino acid change in these large repair proteins is not immediately obvious resulting in them being designated variants of uncertain significance (VUS). One important strategy for resolving this uncertainty is to determine whether the variant results in a non-functional protein. The ability to reconstitute the MMR reaction in vitro has provided an important experimental tool for studying the functional consequences of VUS. However, beyond this repair assay, a number of other experimental methods have been developed that allow us to test the effect of a VUS on discrete biochemical steps or other aspects of MMR function. Here, we describe some of these assays along with the challenges of using such assays to determine the functional consequences of MMR VUS which, in turn, can provide valuable insight into their clinical significance. With increased gene sequencing in patients, the number of identified VUS has expanded dramatically exacerbating this problem for clinicians. However, basic science research laboratories around the world continue to expand our knowledge of the overall MMR molecular mechanism providing new opportunities to understand the functional significance, and therefore pathogenic significance, of VUS.
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