ClinVar Miner

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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