ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1505T>C (p.Ile502Thr) (rs749012012)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491991 SCV000580264 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-14 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000523733 SCV000618391 uncertain significance not provided 2019-01-14 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1505T>C at the cDNA level, p.Ile502Thr (I502T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant has been reported in an individual with colorectal cancer whose tumor was shown to have microsatellite instability and absence of MLH1 and PMS2 proteins on mismatch repair immunohistochemistry; however, the tumor was also positive for MLH1 promoter hypermethylation (Terui 2013). MSH6 Ile502Thr was observed at an allele frequency of 0.02% (4/16512) in individuals of South Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ile502Thr occurs at a position that is not conserved and is located in the mismatch binding domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Ile502Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000491991 SCV000908373 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing
Invitae RCV000792665 SCV000931974 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 502 of the MSH6 protein (p.Ile502Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs749012012, ExAC 0.02%). This variant has been observed in an individual affected with colorectal cancer (PMID: 24100870). ClinVar contains an entry for this variant (Variation ID: 428374). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is 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 and their clinical significance is uncertain. 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.

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