ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1081C>T (p.Arg361Cys) (rs587782651)

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
Ambry Genetics RCV000132064 SCV000187127 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing The p.R361C variant (also known as c.1081C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1081. The arginine at codon 361 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000230863 SCV000283700 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 361 of the MSH6 protein (p.Arg361Cys). 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 (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 142698). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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 RCV000132064 SCV000690171 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-26 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 361 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 13/251080 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 RCV001420719 SCV000695774 uncertain significance not specified 2021-04-23 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1081C>T (p.Arg361Cys) 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 5.2e-05 in 251080 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (5.2e-05 vs 0.00014), allowing no conclusion about variant significance. c.1081C>T has been reported in the literature in individuals affected with prostate cancer or other type of cancer (Rodrigues_2018, Li_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000758606 SCV000887360 likely benign Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.1081C>T has a 1.8% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589862 SCV000889453 uncertain significance not provided 2017-12-18 criteria provided, single submitter clinical testing
GeneDx RCV000589862 SCV001812752 likely benign not provided 2019-02-26 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24983367, 26900293)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000758606 SCV001551706 uncertain significance Lynch syndrome no assertion criteria provided clinical testing The MSH6 p.Arg361Cys variant was not identified in the literature nor was it identified in the COGR, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs587782651) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Color Genomics, Integrated Genetics/Laboratory Corporation of America), and in Cosmic (1x found in prostate tissue). The variant was identified in control databases in 13 of 245822 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 5478 chromosomes (freq: 0.0002), Latino in 11 of 33560 chromosomes (freq: 0.0003), and South Asian in 1 of 30780 chromosomes (freq: 0.00003); it was not observed in the African, European, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Arg361 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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.