ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.746A>C (p.Lys249Thr) (rs61756464)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484112 SCV000571205 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.746A>C at the cDNA level, p.Lys249Thr (K249T) at the protein level, and results in the change of a Lysine to a Threonine (AAG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Lys249Thr 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 Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Lys249Thr occurs at a position that is conserved across species and is located in the connector 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 Lys249Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000566386 SCV000664746 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-17 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001053129 SCV001217375 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-17 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 249 of the MSH2 protein (p.Lys249Thr). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and threonine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 421880). 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.
Color RCV000566386 SCV001345356 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-09 criteria provided, single submitter clinical testing

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