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

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Total submissions: 4

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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 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

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