ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2309T>C (p.Ile770Thr) (rs371718349)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206397 SCV000260483 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 770 of the MSH2 protein (p.Ile770Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs371718349, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 220156). 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.
Ambry Genetics RCV000219799 SCV000274324 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000759827 SCV000566244 uncertain significance not provided 2015-04-09 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2309T>C at the cDNA level, p.Ile770Thr (I770T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ile770Thr was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ile770Thr occurs at a position that is moderately conserved across species and is located in the ATPase domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Ile770Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759827 SCV000889428 uncertain significance not provided 2018-07-17 criteria provided, single submitter clinical testing
Color RCV000219799 SCV000908327 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing

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