ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.118G>A (p.Gly40Ser) (rs63751260)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000627704 SCV000284097 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 40 of the MSH2 protein (p.Gly40Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs63751260, ExAC 0.02%). This variant has been reported in individuals with colorectal or other cancers (PMID: 12792735, 26380806, 31386297, 31666926). ClinVar contains an entry for this variant (Variation ID: 90560). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000236371 SCV000293503 uncertain significance not provided 2019-08-14 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12792735, 26380806, 31386297)
Ambry Genetics RCV000491838 SCV000580530 likely benign Hereditary cancer-predisposing syndrome 2018-10-03 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Color Health, Inc RCV000491838 SCV000684914 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781559 SCV000919699 likely benign not specified 2021-05-24 criteria provided, single submitter clinical testing Variant summary: MSH2 c.118G>A (p.Gly40Ser) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-06 in 227630 control chromosomes (gnomAD). In addition, the variant was reported in Japanese healthy controls at a frequency of 0.0041 (jMorp; PMID: 29069501). The observed variant frequency within the Japanese subpopulation is about 7 times higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), suggesting a benign role for the variant. c.118G>A has been reported in the literature in several individuals of Japanese ancestry, who were affected with colorectal cancer and other (unspecified) tumor phenotypes (example, Yamada_2010, Kochi_2015, Kiyozumi_2019, Terashima_2019), however without strong evidence for causality. These reports therefore do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MSH6 c.3980_3983dupATCA, p.Leu1200fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as likely benign.
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030704 SCV001193626 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research

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