ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.998C>T (p.Thr333Ile) (rs587781983)

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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 RCV000130382 SCV000185238 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000130382 SCV000902968 benign Hereditary cancer-predisposing syndrome 2015-09-18 criteria provided, single submitter clinical testing
GeneDx RCV000212639 SCV000211344 uncertain significance not provided 2018-12-13 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.998C>T at the cDNA level, p.Thr333Ile (T333I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant was observed in an individual with a clinical diagnosis of Hereditary Nonpolyposis Colorectal Cancer syndrome who also harbored a pathogenic MLH1 variant (Simbolo 2015). MSH6 Thr333Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the nuclear localization signal (Gassman 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 Thr333Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000475028 SCV000551279 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 333 of the MSH6 protein (p.Thr333Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (rs587781983, ExAC no frequency). This variant has been observed in an individual affected with Lynch syndrome (PMID: 26300997). However, in that individual a pathogenic allele was also identified in the MLH1 gene, which suggests that this c.998C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 141751). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The isoleucine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Mendelics RCV000708861 SCV000837875 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212639 SCV000889514 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing

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