ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1582A>C (p.Lys528Gln) (rs199744440)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115503 SCV000149412 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1582A>C at the cDNA level, p.Lys528Gln (K528Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAG>CAG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH2 Lys528Gln was not observed in large population cohorts (Lek 2016). This variant is located in the clamp domain and region of interaction with MSH6 and MSH3 (Guerrette 1998, L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Lys528Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000463961 SCV000548188 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 528 of the MSH2 protein (p.Lys528Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 127631). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Ambry Genetics RCV000491225 SCV000580603 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000662996 SCV000785991 uncertain significance Lynch syndrome I 2018-01-26 criteria provided, single submitter clinical testing
Color RCV000491225 SCV001358994 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-21 criteria provided, single submitter clinical testing

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