ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2251G>A (p.Gly751Arg)

dbSNP: rs63751119
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076445 SCV000107473 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000561670 SCV000669869 pathogenic Hereditary cancer-predisposing syndrome 2021-11-30 criteria provided, single submitter clinical testing The p.G751R pathogenic mutation (also known as c.2251G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2251. The glycine at codon 751 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals/families diagnosed with HNPCC (Dieumegard B et al. Br. J. Cancer, 2000 Feb;82:871-80; De Lellis L et al. PLoS One, 2013 Nov;8:e81194; Talbot A et al. BMC Cancer, 2021 May;21:617). Functional analysis of the yeast equivalent alteration (msh2-G770R) have shown intermediate Msh2 expression relative to wild type and deficient DNA repair function (Gammie AE et al. Genetics, 2007 Oct;177:707-21). 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 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc. RCV003452902 SCV004186736 likely pathogenic Lynch syndrome 1 2023-08-08 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics RCV003452902 SCV004196848 pathogenic Lynch syndrome 1 2023-05-10 criteria provided, single submitter clinical testing

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