ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1642G>T (p.Gly548Cys) (rs63750538)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524350 SCV000254389 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 548 of the MSH2 protein (p.Gly548Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Lynch syndrome (PMID: 16395668). ClinVar contains an entry for this variant (Variation ID: 90714). 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 disruptive, 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 RCV000479671 SCV000565195 uncertain significance not provided 2018-04-30 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1642G>T at the cDNA level, p.Gly548Cys (G548C) at the protein level, and results in the change of a Glycine to a Cysteine (GGT>TGT). This variant has been observed in at least one family with HNPCC (Auclair 206). MSH2 Gly548Cys was not observed in large population cohorts (Lek 2016). This variant is located in the region of interaction with MSH6 and MSH3 and in the Clamp domain (Guerrette 1998, 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 Gly548Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000490983 SCV000580428 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000490983 SCV001344570 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-08 criteria provided, single submitter clinical testing

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