ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3573dup (p.Val1192fs) (rs1057517764)

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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 RCV000490868 SCV000580187 pathogenic Hereditary cancer-predisposing syndrome 2018-04-12 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)
Color RCV000490868 SCV000685416 pathogenic Hereditary cancer-predisposing syndrome 2015-12-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000460316 SCV000592650 pathogenic Lynch syndrome 2012-10-17 criteria provided, single submitter clinical testing
GeneDx RCV000413655 SCV000490623 pathogenic not provided 2018-01-25 criteria provided, single submitter clinical testing This duplication of one nucleotide in MSH6 is denoted c.3573dupT at the cDNA level and p.Val1192CysfsX2 (V1192CfsX2) at the protein level. The normal sequence, with the base that is duplicated in braces, is ATTTTT[T]GTTG. The duplication causes a frameshift, which changes a Valine to a Cysteine at codon 1192 and creates a premature stop codon at position 2 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.3573dupT has been observed in one individual with endometrial cancer demonstrating absence of MSH6 protein on immunohistochemistry whose family met revised Bethesda Criteria guidelines, as well as in one individual from a multiple colorectal cancer or Lynch syndrome family (Baglietto 2010, Buchanan 2014). We consider this variant to be pathogenic.
Invitae RCV000684804 SCV000551108 pathogenic Hereditary nonpolyposis colon cancer 2018-06-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val1192Cysfs*2) 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 observed in individuals affected with endometrial cancer and Lynch syndrome (PMID: 24323032, 27064304). ClinVar contains an entry for this variant (Variation ID: 372414). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000413655 SCV000691941 pathogenic not provided no assertion criteria provided clinical testing

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