ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3513_3514del (p.Asp1171fs) (rs63750194)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162609 SCV000213037 pathogenic Hereditary cancer-predisposing syndrome 2017-06-16 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)
GeneDx RCV000221153 SCV000279614 pathogenic not provided 2018-10-22 criteria provided, single submitter clinical testing This deletion of two nucleotides in MSH6 is denoted c.3513_3514delTA at the cDNA level and p.Asp1171GlufsX5 (D1171EfsX5) at the protein level. The normal sequence, with the bases that are deleted in braces, is TTGA[TA]GAGT. The deletion causes a frameshift, which changes an Aspartic Acid to a Glutamic Acid at codon 1171, and creates a premature stop codon at position 5 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.3513_3514delTA has been reported in individuals with colorectal and endometrial cancer, with most tumors demonstrating abnormal mismatch repair protein expression, and is classified as pathogenic by the International Society for Gastrointestinal Hereditary Tumors Incorporated (Steinke 2008, Buchanan 2014, Thompson 2014, Kraus 2015). We consider this variant to be pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074871 SCV000108082 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000630154 SCV000751110 pathogenic Hereditary nonpolyposis colon cancer 2018-01-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp1171Glufs*5) 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 colorectal cancer and endometrial cancer (PMID: 14974087, 18301448, 24323032, 25142776).  ClinVar contains an entry for this variant (Variation ID: 89403). 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 RCV000074871 SCV000713320 pathogenic Lynch syndrome 2017-07-17 criteria provided, single submitter clinical testing The p.Asp1171fs variant in MSH6 has been reported in 3 individuals with Lynch sy ndrome associated cancers (Plaschke 2004, Buchanan 2014 Steinke 2008). This vari ant was absent from large population studies, though the ability of these studie s to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at posit ion 1171 and leads to a premature termination codon 5 amino acids downstream. Th is alteration is then predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In addition, this variant was classified as p athogenic on Sep 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar S CV000108082.2). In summary, this variant meets criteria to be classified as path ogenic for Lynch syndrome in an autosomal dominant manner based upon the predict ed impact to the protein and absence from controls.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000221153 SCV000601576 pathogenic not provided 2017-05-30 criteria provided, single submitter clinical testing

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