ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1910C>G (p.Ser637Cys) (rs1064795992)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482793 SCV000572341 uncertain significance not provided 2016-11-22 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1910C>G at the cDNA level, p.Ser637Cys (S637C) at the protein level, and results in the change of a Serine to a Cysteine (TCC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ser637Cys 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 Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ser637Cys occurs at a position that is conserved in mammals and is located in the ATPase domain and the region of interaction with EXO1 (Lützen 2008, Kansikas 2011). 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 Ser637Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000816301 SCV000956802 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 637 of the MSH2 protein (p.Ser637Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 422780). 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.
Ambry Genetics RCV001013660 SCV001174275 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-21 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV001013660 SCV001348884 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-30 criteria provided, single submitter clinical testing

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