Submissions for variant NM_000251.3(MSH2):c.2075G>A (p.Gly692Glu)

dbSNP: rs63751432

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255143	SCV000322613	likely pathogenic	not provided	2016-06-20	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2075G>A at the cDNA level, p.Gly692Glu (G692E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. However, a different variant at the same position, the non-conservative change MSH2 Gly692Arg, has been reported in individuals with Lynch syndrome, associated with functional defects in vitro, and classified by the International Society for Gastrointestinal Tumours Incorporated (InSiGHT) as likely pathogenic (Isidro 2000, Gammie 2007, Thompson 2013, Houlleberghs 2016). MSH2 Gly692Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Gly692Glu occurs at a position that is conserved across species and is located within the ATPase domain (Lützen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MSH2 Gly692Glu to be a likely pathogenic variant.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000501019	SCV000887417	likely pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2:c.2075G>A has a 96.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Color Diagnostics, LLC DBA Color Health	RCV000772137	SCV000905240	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 692 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer with tumors showing microsatellite instability and lack of MSH2 and MSH6 expression (http://www.umd.be/MSH2/). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same position (p.Gly692Arg, p.Gly692Trp, p.Gly692Val) are known to be disease-causing (Clinvar variation ID: 428477, 90878, 428464, 90880), suggesting the importance of glycine residue at this amino acid position. Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV000803818	SCV000943704	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-11-02	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 10612827; Invitae). 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.Gly692 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10523644, 10612836, 15713769, 23454724, 28135145, 28577310, 29212164). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 265620). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 692 of the MSH2 protein (p.Gly692Glu).
Ambry Genetics	RCV000772137	SCV002726728	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-06-21	criteria provided, single submitter	clinical testing	The p.G692E variant (also known as c.2075G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2075. The glycine at codon 692 is replaced by glutamic acid, an amino acid with similar properties. This alteration was detected in a patient with trifocal colon cancer at age 41 and loss of MSH2/MSH6 on IHC (UMD-MSH2 database). Based on internal structural analysis this alteration destabilizes the ATPase domain (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353568	SCV000592531	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Gly692Glu variant was not identified in the literature nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database”, the ClinVar database and GeneInsight VariantWire database. The variant was only identified in MutDB and UMD (1X as a likely pathogenic variant). The p.Gly692 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Gly692 variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.