ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.532C>T (p.Arg178Cys) (rs730881813)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160711 SCV000211342 uncertain significance not provided 2017-09-20 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.532C>T at the cDNA level, p.Arg178Cys (R178C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). MSH6 Arg178Cys was observed in a patient with epithelial ovarian cancer, but the clinical relevance was not known (Pal 2012). This variant was also reported in a patient with early onset colorectal and endometrial cancer and absence of MSH2 and MSH6 on colon tumor immunohistochemistry; however, this patient also harbored a second variant, MSH2 His639Tyr (Terui 2013). MSH6 Arg178Cys was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg178Cys occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Arg178Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000217717 SCV000277057 likely benign Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing In silico models in agreement (benign);Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
Invitae RCV000456306 SCV000551096 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 178 of the MSH6 protein (p.Arg178Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs730881813, ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 24100870, 23047549, 31386297). ClinVar contains an entry for this variant (Variation ID: 182656). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 24100870). However, this prediction has not been confirmed by published functional studies and its 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 RCV000217717 SCV000685499 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781604 SCV000919776 uncertain significance not specified 2018-11-23 criteria provided, single submitter clinical testing Variant summary: MSH6 c.532C>T (p.Arg178Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 277170 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.532C>T has been reported in the literature in individuals affected with ovarian cancer or colorectal cancer (Pal_2012, Terui_2013). Terui_2013 also reports the variant to co-occur with a likely pathogenic MSH2 variant, c.1915C>T (p.His639Tyr), which provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant three times as uncertain significance and once as benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics RCV000986705 SCV001135788 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030488 SCV001193642 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research

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