ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.900dup (p.Lys301fs) (rs863225421)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213447 SCV000276263 pathogenic Hereditary cancer-predisposing syndrome 2017-11-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000629753 SCV000750709 pathogenic Hereditary nonpolyposis colon cancer 2018-04-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys301Glufs*11) 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 several individuals affected with Lynch syndrome (PMID: 20587412, 27601186). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825624 SCV000966978 pathogenic Lynch syndrome 2018-10-17 criteria provided, single submitter clinical testing The p.Lys301GlufsX11 variant in MSH6 has been reported in 3 individuals with cli nical features of Lynch syndrome and segregated with disease in at least 1 affec ted relative from 1 family (Sjursen 2010, Lagerstedt-Robinson 2016, DeRycke 2017 ). In this family, tumors sampled from individuals exhibited a loss of MSH6 and MSH2 expression by immunohistochemistry (Sjursen 2010). This variant has also be en reported by other clinical laboratories in ClinVar (Variation ID 218080) and was absent from large population studies. The p.Lys301GlufsX11 variant is predic ted to cause a frameshift, which alters the protein?s amino acid sequence beginn ing at position 301 and leads to a premature termination codon 11 amino acids do wnstream. This alteration is then predicted to lead to a truncated or absent pro tein. Loss of function of the MSH6 gene is an established disease mechanism in L ynch syndrome. In summary, this variant meets criteria to be classified as patho genic for Lynch syndrome in an autosomal dominant manner, based upon predicted i mpact to the protein, absence from the general population, functional evidence f rom an established function study and presence in multiple affected individuals. ACMG/AMP Criteria applied: PVS1, PM2, PS3, PS4_Supporting.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202094 SCV000257308 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.