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 colon cancer 2019-11-03 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 affected with colorectal cancer (PMID: 12792735, 26380806). 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 2015-12-02 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.118G>A at the cDNA level, p.Gly40Ser (G40S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). MSH2 Gly40Ser was reported as a germline observation in 1 of 180 Japanese patients with sporadic colorectal cancer and absent in 122 healthy Japanese controls (Yamada 2003). This variant has also been reported in an individual with metachronous colon cancers meeting Amsterdam II criteria for Lynch syndrome found to have a colon tumor with microsatellite instability and absent MSH2 staining (Kochi 2015). MSH2 Gly40Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Gly40Ser occurs at a position that is conserved in mammals and is located within the mismatch binding domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Gly40Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
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 RCV000491838 SCV000684914 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781559 SCV000919699 uncertain significance not specified 2019-10-03 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 0.0045 (jMorp; PMID: 29069501). The observed variant frequency within the Japanese subpopulation is about 8 times higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), suggesting that 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 (Yamada_2010, Kochi_2015, Kiyozumi_2019), however without strong evidence for causality. These reports therefore do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; 3 of them classified the variant as uncertain significance, while 1 called it likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly 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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