ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.998C>T (p.Thr333Ile) (rs587781983)

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Total submissions: 7
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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 2018-11-05 criteria provided, single submitter clinical testing The p.T333I variant (also known as c.998C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 998. The threonine at codon 333 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in one individual with HNPCC who also carries an MLH1 pathogenic mutation (Simbolo M et al. Hered Cancer Clin Pract. 2015 Aug;13:18). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000212639 SCV000211344 uncertain significance not provided 2019-08-21 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with Lynch syndrome who also harbored a pathogenic MLH1 variant (Simbolo 2015); This variant is associated with the following publications: (PMID: 26300997, 28717660, 18523027, 27311873, 31422574)
Invitae RCV000475028 SCV000551279 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-11-01 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
Color Health, Inc RCV000130382 SCV000902968 benign Hereditary cancer-predisposing syndrome 2015-09-18 criteria provided, single submitter clinical testing
Mendelics RCV000986711 SCV001135799 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing

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