ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3203G>A (p.Arg1068Gln) (rs398123230)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000679234 SCV000110153 uncertain significance not provided 2013-06-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131252 SCV000186214 likely benign Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV001083147 SCV000218795 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-08 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000168135 SCV000266208 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000679234 SCV000279106 likely benign not provided 2020-11-06 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26689913, 25503501, 23047549, 23104009, 27978560, 26845104, 22495361, 29625052)
Illumina Clinical Services Laboratory,Illumina RCV000168135 SCV000430974 uncertain significance Lynch syndrome 2016-06-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000217757 SCV000601561 uncertain significance not specified 2017-03-29 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679234 SCV000805880 uncertain significance not provided 2017-12-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131252 SCV000902892 benign Hereditary cancer-predisposing syndrome 2016-09-09 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000168135 SCV001450730 uncertain significance Lynch syndrome 2020-10-15 criteria provided, single submitter clinical testing The MSH6 c.3203G>A (p.Arg1068Gln) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 ( Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer and microsatellite stability or normal mismatch repair immunohistochemistry in the tumor (PMID: 26845104, 27978560). It has also been reported in individuals with sporadic pancreatic ductal adenocarcinoma (PMID: 32659497, 28767289), breast cancer (PMID: 25503501), epithelial ovarian cancer (PMID: 23047549), and pediatric medulloblastoma (PMID: 26580448). Data submitted to ClinVar indicates that this variant did not segregate with disease in a family study (ClinVar Accession: SCV000186214.6). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356423 SCV001551587 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The MSH6 p.Arg1068Gln variant was identified in 3 of 3116 proband chromosomes (frequency: 0.00096) from individuals or families with colorectal cancer, HNPCC, or breast cancer (Hampel 2018, Maxwell 2015, Okkels 2012). The variant was also identified in dbSNP (ID: rs398123230) as "With Uncertain significance, other allele", in ClinVar and Clinvitae (classified as likely benign by Ambry Genetics, Invitae and GeneDx; classified as uncertain significance by EGL, University of Washington, Illumina, Quest Diagnostics and Prevention Genetics), and UMD-LSDB (found to be co-occurring with a pathogenic MSH6 variant: c.2764C>T, p.Arg922X in 2 cases). The variant was not identified in COSMIC, MutDB, Insight Colon Cancer Gene Variant Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in control databases in 31 of 277070 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 24028 chromosomes (freq: 0.0003), Latino in 1 of 34386 chromosomes (freq: 0.00003), European Non-Finnish in 23 of 126620 chromosomes (freq: 0.0002); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Arg1068 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. 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; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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