ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1106C>T (p.Thr369Ile) (rs375974046)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212645 SCV000149277 uncertain significance not provided 2018-05-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1106C>T at the cDNA level, p.Thr369Ile (T369I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant has been observed in an individual with ovarian cancer and colon polyps and in an individual with microsatellite-stable endometrial cancer (Price 2014, Shirts 2016). MSH6 Thr369Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Thr369Ile is located in the mismatch binding domain and the nuclear localization signal (Warren 2007, Gassman 2011, 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 MSH6 Thr369Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115368 SCV000216876 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
University of Washington Department of Laboratory Medicine,University of Washington RCV000210148 SCV000266199 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000415687 SCV000493756 uncertain significance Lynch syndrome I 2015-12-04 criteria provided, single submitter clinical testing
Invitae RCV000528613 SCV000624612 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 369 of the MSH6 protein (p.Thr369Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs375974046, ExAC 0.006%). This variant has been reported in an individual affected with ovarian cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 127554). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). An algorithm developed specifically for the MSH6 gene (PMID: 23621914) suggests that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. 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 RCV000662663 SCV000785352 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-07-11 criteria provided, single submitter clinical testing

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