ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
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 colon cancer 2018-11-28 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 (rs199744440, ExAC no frequency) and has not been reported in the literature in individuals with a MSH2-related disease. 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. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000491225 SCV000580603 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Other data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Counsyl RCV000662996 SCV000785991 uncertain significance Lynch syndrome I 2018-01-26 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.