ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2417C>T (p.Thr806Ile) (rs758889557)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205485 SCV000259450 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 806 of the MSH2 protein (p.Thr806Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs758889557, ExAC 0.003%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 219534). 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. 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.
GeneDx RCV000480146 SCV000566944 uncertain significance not provided 2017-09-27 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2417C>T at the cDNA level, p.Thr806Ile (T806I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Thr806Ile was not observed at a significant allele frequency in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Thr806Ile occurs at a position that is conserved across species and is located in the ATPase domain (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Thr806Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568311 SCV000662317 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000568311 SCV000685040 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing
Mendelics RCV000708843 SCV000837852 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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