Submissions for variant NM_000251.3(MSH2):c.2039G>A (p.Arg680Gln)

gnomAD frequency: 0.00001  dbSNP: rs1203462814

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000702670	SCV000831533	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-05	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 680 of the MSH2 protein (p.Arg680Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer, pancreatic cancer, and/or rectal cancer (PMID: 28445943, 31248605, 35449176). ClinVar contains an entry for this variant (Variation ID: 579393). 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 95%. 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.
Mendelics	RCV000708840	SCV000837847	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759108	SCV000888214	uncertain significance	not provided	2022-08-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000013 (2/152088 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with rectal cancer (PMID: 28445943 (2017)). 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.
Ambry Genetics	RCV001014159	SCV001174839	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-25	criteria provided, single submitter	clinical testing	The p.R680Q variant (also known as c.2039G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2039. The arginine at codon 680 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in a Chinese individual with MSH2-/MSH6- rectal cancer diagnosed at age 30 (Zhang J et al. Oncotarget, 2017 Apr;8:24533-24547). 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 Jan;108:163-175). Based on internal structural analysis, this variant is anticipated to result in a change in ATP binding (Gupta S et al. Nat Struct Mol Biol, 2011 Dec;19:72-8). 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 conflicting at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226374	SCV003922585	uncertain significance	not specified	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2039G>A (p.Arg680Gln) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251446 control chromosomes. c.2039G>A has been reported in the literature in an individual affected with Colorectal Cancer with loss of MSH2 and MSH6 in tumor tissue (Zhang_2017) and in a patient with Prostate Cancer, without strong evidence for causality (Wei_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.
All of Us Research Program, National Institutes of Health	RCV000708840	SCV004832964	uncertain significance	Lynch syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 680 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). Functional studies have shown that this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with breast cancer (PMID: 32091409) and rectal cancer (PMID: 28445943). 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.