ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2725A>C (p.Lys909Gln) (rs879254253)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236832 SCV000293973 uncertain significance not provided 2016-02-16 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2725A>C at the cDNA level, p.Lys909Gln (K909Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Lys909Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Lys909Gln occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in the helix-turn-helix domain (Lützen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Lys909Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000812576 SCV000952894 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 909 of the MSH2 protein (p.Lys909Gln). The lysine residue is weakly 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: 246423). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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