ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.166G>A (p.Glu56Lys) (rs587779102)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000580136 SCV000684962 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
GeneDx RCV000657006 SCV000292792 uncertain significance not provided 2018-02-01 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.166G>A at the cDNA level, p.Glu56Lys (E56K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant was observed in at least one individual with ovarian cancer (Pal 2012). MSH2 Glu56Lys was not observed in large population cohorts (Lek 2016). This variant is located within the mismatch binding domain (L?tzen 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 Glu56Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000122982 SCV000166265 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 56 of the MSH2 protein (p.Glu56Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549). Additionally, this variant has been observed in an individual with colorectal cancer (Invitae). However, in that individual, a pathogenic allele was also identified in MSH2, which suggests that this c.166G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 135854). 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: "Tolerated"; 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000235661 SCV000539688 uncertain significance not specified 2016-06-16 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in proband with ovarian cancer; ClinVar: 1 VUS

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