Submissions for variant NM_000251.3(MSH2):c.488T>A (p.Val163Asp)

dbSNP: rs63750214

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076610	SCV000107646	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000492044	SCV000580473	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-06	criteria provided, single submitter	clinical testing	The p.V163D pathogenic mutation (also known as c.488T>A), located in coding exon 3 of the MSH2 gene, results from a T to A substitution at nucleotide position 488. The valine at codon 163 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant has been identified in multiple individuals who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability and/or loss of MSH2 expression by immunohistochemistry (Ward, R et al. J Cancer Res Clin Oncol. 2002 Aug;128(8):403-11; Rhees, J et al. Fam Cancer. 2014 Jun;13(2):219-25; Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463; Ambry internal data). In an in vitro complementation assay, this variant was determined to be functionally deficient (Drost M et al. Genet Med, 2019 07;21:1486-1496). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). 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 variant is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000492044	SCV000690112	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-09-01	criteria provided, single submitter	clinical testing	This missense variant replaces valine with aspartic acid at codon 163 in the DNA binding domain of the MSH2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ‚â•0.7, PMID: 27666373). Functional studies have shown that this variant impairs DNA mismatch repair activity (MMR) (PMID: 26951660, 30504929). This variant has been reported in two individuals affected with Lynch syndrome (PMID: 12200596, 17192056, 18383312). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003593902	SCV004292475	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 163 of the MSH2 protein (p.Val163Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12200596, 24114314; internal data). ClinVar contains an entry for this variant (Variation ID: 91107). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. This variant disrupts the p.Val163 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been observed in individuals with MSH2-related conditions (PMID: 29212164), which suggests that this may be a clinically significant amino acid residue. 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.
Baylor Genetics	RCV004566934	SCV005053520	likely pathogenic	Lynch syndrome 1	2023-12-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998195	SCV005623670	pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing	The MSH2 c.488T>A (p.Val163Asp) variant has been reported in the published literature in individuals affected with Lynch syndrome whose tumors showed high microsatellite instability and/or loss of MSH2 on immunohistochemistry (PMIDs: 12200596 (2002), 17192056 (2006), 18383312 (2008), and 24114314 (2014)). Functional studies have indicated that this variant has a deleterious effect on DNA mismatch repair activity (PMIDs: 26951660 (2016), 30504929 (2018), and 33357406 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.