ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2147C>T (p.Thr716Ile) (rs587782805)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132365 SCV000187455 likely benign Hereditary cancer-predisposing syndrome 2019-03-22 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000212659 SCV000211292 uncertain significance not provided 2021-03-10 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast or pancreatic cancer (Tung 2015, Shindo 2017, Hu 2020); This variant is associated with the following publications: (PMID: 28767289, 25186627, 32659497)
Counsyl RCV000411918 SCV000488260 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-02-12 criteria provided, single submitter clinical testing
Invitae RCV000468830 SCV000551149 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 716 of the MSH6 protein (p.Thr716Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 25186627) and in an individual affected with pancreatic cancer (PMID: 28767289). ClinVar contains an entry for this variant (Variation ID: 142897). 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 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.
Color Health, Inc RCV000132365 SCV000690245 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-13 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 716 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with pancreatic cancer (PMID: 28767289, 32659497) and breast cancer (PMID: 25186627). This variant has been identified in 1/31398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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