ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160711 SCV000211342 uncertain significance not provided 2020-08-05 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal or ovarian cancer (Pal 2012, Terui 2013, Kiyozumi 2019); This variant is associated with the following publications: (PMID: 23047549, 24100870, 31386297, 31470354)
Ambry Genetics RCV000217717 SCV000277057 likely benign Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign)
Invitae RCV000456306 SCV000551096 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-09-13 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 Health, Inc RCV000217717 SCV000685499 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-29 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 178 of the MSH6 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ovarian cancer, colorectal cancer, and Lynch syndrome (PMID: 23047549, 24100870, 31386297); in one individual this variant co-occurs with a pathogenic MSH2 variant (PMID: 24100870). This variant has also been identified in 6/282830 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160711 SCV001469832 uncertain significance not provided 2020-05-04 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.