ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.376G>A (p.Gly126Ser)

gnomAD frequency: 0.00001  dbSNP: rs767371843
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166502 SCV000217301 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-30 criteria provided, single submitter clinical testing The p.G126S variant (also known as c.376G>A), located in coding exon 3 of the MSH2 gene, results from a G to A substitution at nucleotide position 376. The glycine at codon 126 is replaced by serine, an amino acid with similar properties. This alteration was detected in conjunction with a pathogenic MSH2 mutation (phase unknown) in an Italian individual meeting Amsterdam I criteria, whose tumor demonstrated microsatellite instability and loss of MSH2 protein expression (De Lellis L et al. PLoS ONE, 2013 Nov;8:e81194). This alteration has also been detected in a Hispanic patient diagnosed with a Lynch syndrome-associated cancer (Sunga AY et al. Cancer Genet. 2017 Apr;212-213:1-7). 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 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 available evidence, the clinical significance of this alteration remains unclear.
Invitae RCV000199020 SCV000254419 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-05 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 126 of the MSH2 protein (p.Gly126Ser). This variant is present in population databases (rs767371843, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 24278394, 28449805). ClinVar contains an entry for this variant (Variation ID: 186849). 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%. 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.
Fulgent Genetics, Fulgent Genetics RCV000515190 SCV000611401 uncertain significance Lynch syndrome 1; Mismatch repair cancer syndrome 1; Muir-Torré syndrome 2017-05-23 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000166502 SCV001349879 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-27 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003995507 SCV004830098 uncertain significance Lynch syndrome 2024-01-03 criteria provided, single submitter clinical testing

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