Submissions for variant NM_000251.3(MSH2):c.2015T>G (p.Met672Arg)

dbSNP: rs786203126

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166295	SCV000217079	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	The p.M672R variant (also known as c.2015T>G), located in coding exon 13 of the MSH2 gene, results from a T to G substitution at nucleotide position 2015. The methionine at codon 672 is replaced by arginine, an amino acid with similar properties. The yeast equivalent of this variant demonstrated an increased mutation rate in a multiplexed functional assay performed using Saccharomyces cerevisiae (Ollodart AR et al. Genetics, 2021 Jun;218). 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). This alteration was seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). 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.
Invitae	RCV000468110	SCV000548249	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-18	criteria provided, single submitter	clinical testing	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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). Experimental studies have shown that this missense change affects MSH2 function (PMID: 33848333). 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. ClinVar contains an entry for this variant (Variation ID: 186664). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 672 of the MSH2 protein (p.Met672Arg).
Color Diagnostics, LLC DBA Color Health	RCV000166295	SCV000685000	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with arginine at codon 672 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). 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 not been reported in individuals affected with MSH2-related disorders in the literature. 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.
Sema4, Sema4	RCV000166295	SCV002534440	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-02	criteria provided, single submitter	curation
GeneDx	RCV003227685	SCV003924682	uncertain significance	not provided	2023-04-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are conflicting: some exhibit restored mismatch repair (MMR) function in an MSH2 knockout cell line and others show increased mutation rate compared to wildtype in yeast (Jia et al., 2020; Ollodart et al., 2021); Observed in individuals with a personal history of breast cancer (Akcay et al., 2020); This variant is associated with the following publications: (PMID: 18822302, 21120944, 33357406, 32658311, 33848333)
All of Us Research Program, National Institutes of Health	RCV003995498	SCV004825172	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with arginine at codon 672 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). 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 not been reported in individuals affected with MSH2-related disorders in the literature. 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.