ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.103C>G (p.Arg35Gly) (rs1060502034)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483915 SCV000572553 uncertain significance not provided 2018-12-14 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.103C>G at the cDNA level, p.Arg35Gly (R35G) at the protein level, and results in the change of an Arginine to a Glycine (CGC>GGC). This variant has been observed in at least one individual with breast cancer (Xie 2017). MSH2 Arg35Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Arg35Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000579393 SCV000684895 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
Invitae RCV000629871 SCV000750827 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 35 of the MSH2 protein (p.Arg35Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. 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: 422949). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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.

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