ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1319T>C (p.Leu440Pro) (rs587779084)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076121 SCV000107137 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000491100 SCV000580448 pathogenic Hereditary cancer-predisposing syndrome 2020-08-07 criteria provided, single submitter clinical testing The p.L440P pathogenic mutation (also known as c.1319T>C), located in coding exon 8 of the MSH2 gene, results from a T to C substitution at nucleotide position 1319. The leucine at codon 440 is replaced by proline, an amino acid with similar properties. This variant has been identified in probands who met Amsterdam criteria for Lynch syndrome and had colorectal tumors demonstrating either high microsatellite instability (MSI-H) or loss of both MSH2/MSH6 expression on immunohistochemistry (IHC) (Ambry internal data; Bozzao C et al. Cancer, 2011 Sep;117:4325-35). In a functional study performed in yeast, t<span style="background-color:initial">his alteration was found to have reduced mismatch repair (<span style="background-color:initial">MMR) activity, a 50% reduction in MSH2 protein expression when compared to wild type MSH2<span style="background-color:initial">, and loss of the MSH6/MSH3 subunit interactions (Gammie AE et al. Genetics. 2007 Oct;177(2):707-21). In an in vitro complementation assay, this variant was reported to have reduced MMR activity when <span style="background-color:initial">compared to wild type MSH2 (Drost M et al. Genet. Med., 2019 07;21:1486-1496).<span style="background-color:initial"> This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Health, Inc RCV000491100 SCV000905226 likely pathogenic Hereditary cancer-predisposing syndrome 2021-02-03 criteria provided, single submitter clinical testing This missense variant replaces leucine with proline at codon 440 in the MSH3/MSH6 interaction domain of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study in yeast has shown the mutant protein to exhibit decreased expression levels, partially reduced mismatch repair activity and ability to interact with MSH3/MSH6 proteins (PMID: 17720936). This variant has also been shown to result in >80% decrease in mismatch repair activity of MSH2 protein in an in vitro complementation assay (PMID: 30504929). A 6-thioguanine sensitivity assay in Msh2-deficient haploid human cells has indicated that this variant is likely to impair DNA mismatch repair activity (PMID: 33357406). This variant has been reported in multiple individuals affected with colorectal cancer, with tumors showing microsatellite instability and loss of MSH2/MSH6 protein expression (PMID: 21387278; ClinVar SCV000580448.4; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.