ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.257C>T (p.Thr86Ile) (rs768444916)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572033 SCV000664870 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-17 criteria provided, single submitter clinical testing The p.T86I variant (also known as c.257C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 257. The threonine at codon 86 is replaced by isoleucine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with mismatch repair proficient colon cancer and multiple colon polyps at age 44 (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This amino acid position is poorly 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.
Invitae RCV000629809 SCV000750765 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 86 of the MSH6 protein (p.Thr86Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with colon cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 480918). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Color Health, Inc RCV000572033 SCV000903779 likely benign Hereditary cancer-predisposing syndrome 2016-01-12 criteria provided, single submitter clinical testing

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