Submissions for variant NM_000251.3(MSH2):c.2768T>A (p.Val923Glu)

gnomAD frequency: 0.00001  dbSNP: rs146421227

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533753	SCV000625411	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 923 of the MSH2 protein (p.Val923Glu). This variant is present in population databases (rs146421227, gnomAD 0.0009%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 12112654, 17101317, 18566915, 21431882). ClinVar contains an entry for this variant (Variation ID: 91043). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MSH2 function (PMID: 17101317, 18951462, 21431882, 33357406). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001016538	SCV001177501	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-01	criteria provided, single submitter	clinical testing	The p.V923E variant (also known as c.2768T>A), located in coding exon 16 of the MSH2 gene, results from a T to A substitution at nucleotide position 2768. The valine at codon 923 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant has been reported in several Lynch syndrome families meeting Amsterdam criteria and/or suspected Lynch syndrome families (Bisgaard ML et al. Hum. Mutat., 2002 Jul;20:20-7; Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17; Nilbert M et al. Fam. Cancer, 2009 Jun;8:75-83); however, this alteration has also been observed in an individual whose colorectal tumor demonstrated normal mismatch repair protein expression on immunohistochemistry (IHC) (Ambry internal data). This alteration demonstrated no reduction in mismatch repair capability compared to wildtype in vitro and caused mild reduction in mismatch binding and release capacity of MSH2 (Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17; Ollila S et al. Hum. Mutat., 2008 Nov;29:1355-63). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001016538	SCV001353063	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glutamic acid at codon 923 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). Experimental functional studies have provided inconsistent results for this variant (PMID 17101317, 18951462, 21431882, 33357406). This variant has been reported in individuals affected with Lynch Syndrome in the literature (PMID 12112654, 17101317, 18566915, 21431882). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998194	SCV005623665	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	The MSH2 c.2768T>A (p.Val923Glu) variant has been reported in the published literature in individuals with colorectal cancer (PMIDs: 18566915 (2009), 12112654 (2002)), and one of which was also positive for a MSH6 variant (PMID: 21431882 (2011)). Additionally, the variant was reported in at least one reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ MSH2)). Functional studies have reported conflicting results on the effect this variant has on protein function (PMIDs: 33357406 (2021), 22949387 (2013), 18951462 (2008), 17101317 (2006)). The frequency of this variant in the general population, 0.0000066 (1/152198 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, we are unable to determine the clinical significance of this variant.
CSER _CC_NCGL, University of Washington	RCV000148640	SCV000190355	uncertain significance	Colorectal cancer, non-polyposis	2014-06-01	no assertion criteria provided	research