ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.2763_2764AG[1] (p.Glu922fs) (rs63750833)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074805 SCV000108016 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000202199 SCV000149311 pathogenic not provided 2018-11-09 criteria provided, single submitter clinical testing This deletion of two nucleotides in MSH6 is denoted c.3155_3156delAG at the cDNA level and p.Glu1052ValfsX13 (E1052VfsX13) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GTAG[delAG]TGTA. The deletion causes a frameshift, which changes a Glutamic Acid to a Valine at codon 1052, and creates a premature stop codon at position 13 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.3155_3156delAG has been published in association with Lynch syndrome (Hampel 2005, Baglietto 2010) and is considered pathogenic.
Ambry Genetics RCV000115402 SCV000214795 pathogenic Hereditary cancer-predisposing syndrome 2018-05-10 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000524154 SCV000260422 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1052Valfs*13) 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 an individual with colorectal cancer (PMID: 15872200), and an individual with Lynch syndrome (PMID: 20028993). ClinVar contains an entry for this variant (Variation ID: 89340). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000074805 SCV000695840 pathogenic Lynch syndrome 2017-07-19 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3155_3156delAG (p.Glu1052Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3202C>T, p.Arg1068X; c.3261delC, p.Phe1088fs). One in silico tool predicts a damaging outcome for this variant. The variant of interest has not been found in a large, broad control population, ExAC in 118918 control chromosomes. This variant was reported in multiple affected individuals (Hampel_MLH1_NEJM_2005, susswein_MLH1_GM_2016, Espenschied_PMS2_JCO_2017). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202199 SCV000889483 pathogenic not provided 2016-07-07 criteria provided, single submitter clinical testing
Color RCV000115402 SCV001340970 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202199 SCV000257234 pathogenic not provided no assertion criteria provided research

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