Submissions for variant NM_000251.3(MSH2):c.1319T>C (p.Leu440Pro)

dbSNP: rs587779084

Total submissions: 4

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, this alteration was found to have reduced mismatch repair (MMR) activity, a 50% reduction in MSH2 protein expression when compared to wild type MSH2, 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 compared to wild type MSH2 (Drost M et al. Genet. Med., 2019 07;21:1486-1496). 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 Diagnostics, LLC DBA Color Health	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.
Invitae	RCV002514349	SCV003524640	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-02-15	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu440 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17720936, 33357406). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 90625). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 21387278). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 440 of the MSH2 protein (p.Leu440Pro).