Submissions for variant NM_000251.2(MSH2):c.1012G>A (p.Gly338Arg) (rs63751004)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000075998	SCV000548158	uncertain significance	Lynch syndrome	2016-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 338 of the MSH2 protein (p.Gly338Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (rs63751004, ExAC no frequency). This variant has been reported in an individual affected with hereditary nonpolyposis colon cancer (PMID: 16736289). ClinVar contains an entry for this variant (Variation ID: 90503). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH2 gene (PMID: 22290698), suggest that this missense change is likely to be deleterious. However, these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000500876	SCV000592485	uncertain significance	not specified	2016-08-19	criteria provided, single submitter	clinical testing

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