ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.361C>T (p.Arg121Cys) (rs763593669)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205461 SCV000260003 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 121 of the MSH6 protein (p.Arg121Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs763593669, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 219881). 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 disruptive, 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.
GeneDx RCV000483247 SCV000571482 uncertain significance not provided 2016-08-24 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.361C>T at the cDNA level, p.Arg121Cys (R121C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). MSH6 Arg121Cys has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in gliomas (Suzuki 2015). MSH6 Arg121Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg121Cys occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the PWWP domain (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Arg121Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000567183 SCV000669910 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000567183 SCV000685421 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-03 criteria provided, single submitter clinical testing
Counsyl RCV000662497 SCV000785019 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-03-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483247 SCV001134437 uncertain significance not provided 2019-01-27 criteria provided, single submitter clinical testing

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