ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.533G>A (p.Arg178His) (rs786204186)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168249 SCV000218920 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 178 of the MSH6 protein (p.Arg178His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 188269). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). The histidine 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. 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.
Ambry Genetics RCV000220140 SCV000276282 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000411795 SCV000489239 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-09-07 criteria provided, single submitter clinical testing
GeneDx RCV000759151 SCV000565211 uncertain significance not provided 2016-05-10 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.533G>A at the cDNA level, p.Arg178His (R178H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Arg178His 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 Histidine share similar properties, this is considered a conservative amino acid substitution. MSH6 Arg178His occurs at a position that is not conserved and is located in the PWWP domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Arg178His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000220140 SCV000685500 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759151 SCV000888292 uncertain significance not provided 2018-04-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781571 SCV000919723 uncertain significance not specified 2018-11-13 criteria provided, single submitter clinical testing Variant summary: MSH6 c.533G>A (p.Arg178His) results in a non-conservative amino acid change located in the PWWP domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246216 control chromosomes (gnomAD) . The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.533G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000411795 SCV001135789 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing

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