ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3787C>T (p.Arg1263Cys) (rs367912290)

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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 RCV000164843 SCV000215526 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-18 criteria provided, single submitter clinical testing The p.R1263C variant (also known as c.3787C>T), located in coding exon 8 of the MSH6 gene, results from a C to T substitution at nucleotide position 3787. The arginine at codon 1263 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000485038 SCV000568016 uncertain significance not provided 2020-01-22 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with colorectal and other cancers (Yurgelun 2017, Li 2020); This variant is associated with the following publications: (PMID: 25583476, 23621914, 31391288, 28135145)
Invitae RCV000559935 SCV000624917 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1263 of the MSH6 protein (p.Arg1263Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs367912290, ExAC 0.02%). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 89461). 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 cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. However, an algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be disruptive (PMID: 23621914). 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.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659897 SCV000781795 likely benign Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
Counsyl RCV000659897 SCV000786062 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-02-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164843 SCV000911159 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485038 SCV001134442 uncertain significance not provided 2018-12-12 criteria provided, single submitter clinical testing

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