ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1634_1635del (p.Lys545fs) (rs267608064)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129244 SCV000184003 pathogenic Hereditary cancer-predisposing syndrome 2017-04-11 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 RCV000129244 SCV000905450 pathogenic Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing
GeneDx RCV000202281 SCV000565783 pathogenic not provided 2018-01-31 criteria provided, single submitter clinical testing This deletion of two nucleotides in MSH6 is denoted c.1634_1635delAA at the cDNA level and p.Lys545ArgfsX17 (K545RfsX17) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAAA[delAA]GAGG. The deletion causes a frameshift, which changes a Lysine to an Arginine at codon 545, and creates a premature stop codon at position 17 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.1634_1635delAA has been reported in at least one individual with endometrial cancer, in an individual with a personal history of Lynch syndrome-associated cancer and/or colon polyps, as well as in the compound heterozygous state in a patient with constitutional mismatch repair deficiency (Peters 2009, Yurgelun 2015, Ring 2016). We consider this variant to be pathogenic.
Invitae RCV000558194 SCV000624671 pathogenic Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys545Argfs*17) 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 the literature in an individual with colorectal cancer (PMID: 26681312) and in an individual with lymphoblastic lymphoma (PMID: 19194194). ClinVar contains an entry for this variant (Variation ID: 140961). 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 RCV000202281 SCV000257215 pathogenic not provided no assertion criteria provided research
Mendelics RCV000708867 SCV000837882 likely pathogenic Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202281 SCV000601511 pathogenic not provided 2015-02-26 criteria provided, single submitter clinical testing

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