Submissions for variant NM_000251.3(MSH2):c.2132G>A (p.Arg711Gln)

gnomAD frequency: 0.00001  dbSNP: rs138465383

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563683	SCV000673913	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-01	criteria provided, single submitter	clinical testing	The p.R711Q variant (also known as c.2132G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2132. The arginine at codon 711 is replaced by glutamine, an amino acid with highly similar properties. Using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as uncertain significance (Shirts BH et al. Am. J. Hum. Genet., 2018 07;103:19-29). In a methylation tolerance-based functional assay, this alteration was classified as a variant of unknown significance (Bouvet D et al. Gastroenterology, 2019 08;157:421-431). 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 neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This alteration was also identified in an individual diagnosed with colon, stomach and breast cancer (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758589	SCV000887338	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2:c.2132G>A has a 63.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 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.
Invitae	RCV000792263	SCV000931545	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 711 of the MSH2 protein (p.Arg711Gln). This variant is present in population databases (rs138465383, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of MSH2-related conditions (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 485849). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 30998989). This variant disrupts the p.Arg711 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20937110; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Diagnostics, LLC DBA Color Health	RCV000563683	SCV001352950	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 711 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). One functional study has shown that the variant is potentially damaging for DNA mismatch repair based on a methylation tolerance assay (PMID: 30998989) while another study in yeast reported this variant having a mild increase in mutation rate (PMID: 33848333). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251480 chromosomes 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.
GeneDx	RCV001545453	SCV001764786	uncertain significance	not provided	2019-04-19	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30998989)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356554	SCV001551758	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Arg711Gln variant was not identified in the literature. The variant was identified in dbSNP (ID: rs138465383) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics), and the UMD-LSDB database. The variant was identified in control databases in 2 of 246250 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 111702 chromosomes (freq: 0.000009) and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Arg711 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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 uncertain significance.