ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.581T>C (p.Ile194Thr) (rs730881778)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212589 SCV000211239 uncertain significance not provided 2014-10-09 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.581T>C at the cDNA level, p.Ile194Thr (I194T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). In a yeast based functional assay, MSH2 Ile194Thr was not shown to cause any mismatch repair defects (Martinez 2010). MSH2 Ile194Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ile194Thr occurs at a position that is well conserved across species and is located in the connector domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Ile194Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160638 SCV000216832 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000556928 SCV000625439 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 194 of the MSH2 protein (p.Ile194Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs730881778, ExAC 0.009%) but has not been reported in the literature in individuals with a MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182598). An experimental study has shown that this variant does not significantly alter the mismatch repair activity of the MSH2 protein (PMID: 20176959) In summary, this variant is a rare missense change that does not affect 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.
Color RCV000160638 SCV000903531 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-31 criteria provided, single submitter clinical testing

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