ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.97A>C (p.Thr33Pro) (rs63751107)

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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 RCV000129083 SCV000183786 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-28 criteria provided, single submitter clinical testing Conflicting evidence
Color RCV000129083 SCV000292198 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
GeneDx RCV000656871 SCV000292614 uncertain significance not provided 2018-12-06 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.97A>C at the cDNA level, p.Thr33Pro (T33P) at the protein level, and results in the change of a Threonine to a Proline (ACA>CCA). This variant has been reported in at least one patient with endometrial cancer and one with rectal cancer (Ollila 2006, Hampel 2006, Chubb 2015). This endometrial tumor was shown to have microsatellite instability (MSI-H); however immunohistochemistry (IHC) revealed the presence of MSH2 and MSH6 proteins (Ollila 2006). Functional studies report that this variant is associated with decreased in vitro mismatch repair (MMR) activity compared to wild type, slightly reduced ATP-dependent release of DNA and weak MMR defects in vivo; however, interaction with MSH6, expression in colon carcinoma cells, protein stability, and mismatch binding were similar to wild type (Ollila 2006, Ollila 2008, Martinez 2010). In addition, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as having uncertain significance (Thompson 2014). MSH2 Thr33Pro was observed at an allele frequency of 0.01% (4/31,200) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located in the mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MSH2 Thr33Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000627734 SCV000548234 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 33 of the MSH2 protein (p.Thr33Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant is present in population databases (rs63751107, ExAC 0.01%). This variant has been reported in individuals affected with hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 16237223, 16885385, 25559809). ClinVar contains an entry for this variant (Variation ID: 91267). Experimental studies have shown that this variant causes slightly reduced mismatch repair activity in the MSH2 protein (PMID: 18951462, 17101317, 20176959). 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000236043 SCV000712785 uncertain significance not specified 2016-12-21 criteria provided, single submitter clinical testing The p.Thr33Pro variant in MSH2 has been reported in 4 individuals with Lynch Syn drome-related cancers (Hedge 2005, Hampel 2006, Ollila 2006, Chubb 2015). Functi onal studies (microsatellite instability, immunohistochemistry, mismatch repair, expression and interaction assays) provide conflicting evidence on whether the p.Thr33Pro variant impacts protein function (Ollila 2006, Ollila 2008, Kansikas 2011, Martinez 2010). This variant has also been identified in 4/35232 of Europ ean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst; dbSNP rs63751107). Computational prediction tools and conservation an alysis suggest that the p.Thr33Pro variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In addition, thi s variant was classified as a variant of uncertain significance on Sept. 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107811.2). In summa ry, the clinical significance of the p.Thr33Pro variant is uncertain.
Counsyl RCV000662483 SCV000784981 uncertain significance Lynch syndrome I 2017-02-27 criteria provided, single submitter clinical testing

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