Submissions for variant NM_000251.2(MSH2):c.1681G>A (p.Glu561Lys) (rs63750328)

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Total submissions: 6

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524354	SCV000284120	uncertain significance	Hereditary nonpolyposis colon cancer	2018-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 561 of the MSH2 protein (p.Glu561Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs63750328, ExAC 0.003%). This variant has been reported in an individual from a family affected with Lynch syndrome (PMID: 16395668), and in individuals in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 90745). 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) all suggest that this missense change is likely to be tolerated, although these predictions have not been confirmed by published functional studies. In addition, minigene analysis of patient lymphoblast RNA shows that this variant does not lead to aberrant splicing (PMID: 16395668). 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.
Counsyl	RCV000410128	SCV000487855	uncertain significance	Lynch syndrome I	2015-11-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000484663	SCV000567206	uncertain significance	not provided	2018-02-20	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1681G>A at the cDNA level, p.Glu561Lys (E561K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant was observed in at least one individual with a personal and/or family history suspicious for Lynch syndrome, and an RT-PCR assay using this individual's RNA did not reveal any defect in splicing (Auclair 2006). MSH2 Glu561Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Lever domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Glu561Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000568086	SCV000669724	uncertain significance	Hereditary cancer-predisposing syndrome	2017-09-22	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color	RCV000568086	SCV000690015	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-24	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000568086	SCV000822046	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing

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