ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3768T>G (p.Tyr1256Ter) (rs63751058)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074926 SCV000108139 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000491038 SCV000580173 pathogenic Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing The p.Y1256* pathogenic mutation (also known as c.3768T>G), located in coding exon 8 of the MSH6 gene, results from a T to G substitution at nucleotide position 3768. This changes the amino acid from a tyrosine to a stop codon within coding exon 8. This mutation was initially reported in two Caucasian women with endometrial cancer, one of whom also had colorectal cancer diagnosed at age 40 and a family history meeting Amsterdam II criteria (Hampel H et al. Cancer Res. 2006 Aug;66(15):7810-7; Hampel H et al. Cancer Res. 2007 Oct;67(19):9603). This alteration has since been reported in a Caucasian Israeli family with Lynch syndrome (Goldberg Y et al. Clin. Genet. 2015 Jun;87(6):549-53), and in an additional patient with endometrioid endometrial cancer diagnosed at age 51 (Goodfellow PJ et al. J. Clin. Oncol. 2015 Dec;33(36):4301-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000202271 SCV000616790 pathogenic not provided 2018-04-09 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.3768T>G at the cDNA level and p.Tyr1256Ter (Y1256X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAT>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least three women with endometrial cancer, one of whom also had colorectal cancer, with studied tumors demonstrating microsatellite instability and/or loss of MSH6 protein expression on immunohistochemistry (Hampel 2006, Hampel 2007, Goodfellow 2015). We consider this variant to be pathogenic.
Invitae RCV000546623 SCV000624913 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr1256*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with endometrial cancer and suspected Lynch syndrome (PMID: 16885385, 26552419, 25430799). ClinVar contains an entry for this variant (Variation ID: 89458). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Color RCV000491038 SCV001345238 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202271 SCV000257278 pathogenic not provided no assertion criteria provided research

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.