Submissions for variant NM_000251.2(MSH2):c.1831G>A (p.Val611Met) (rs369385048)

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Total submissions: 6

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000232146	SCV000284124	uncertain significance	Hereditary nonpolyposis colon cancer	2018-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces valine with methionine at codon 611 of the MSH2 protein (p.Val611Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs369385048, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 237376). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	RCV000481079	SCV000567929	uncertain significance	not provided	2017-11-29	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1831G>A at the cDNA level, p.Val611Met (V611M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Val611Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. MSH2 Val611Met is located in the Lever domain and the region of interaction with MSH6, MSH3, and EXO1 (Guerrette 1998, L?tzen 2008, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether MSH2 Val611Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000575973	SCV000662227	uncertain significance	Hereditary cancer-predisposing syndrome	2016-11-14	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color	RCV000575973	SCV000684982	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000662772	SCV000785573	uncertain significance	Lynch syndrome I	2017-09-22	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000575973	SCV000822050	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing

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