ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2111T>C (p.Ile704Thr) (rs564657106)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222410 SCV000277734 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000227730 SCV000284137 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 704 of the MSH2 protein (p.Ile704Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs564657106, ExAC 0.009%). This variant has been reported in individuals in the Universal Mutation Database (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 233375). Experimental studies have shown that this missense change does not disrupt MSH2 mismatch-repair activity (PMID: 26951660). 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.
Counsyl RCV000411876 SCV000489282 uncertain significance Lynch syndrome I 2016-09-13 criteria provided, single submitter clinical testing
GeneDx RCV000483732 SCV000572481 uncertain significance not provided 2018-01-19 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2111T>C at the cDNA level, p.Ile704Thr (I704T) 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 Ile704Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Ile704Thr is located in the ATPase domain (Lutzen 2008, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Ile704Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000222410 SCV000685012 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Mendelics RCV000708841 SCV000837848 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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