ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1606_1609AGTA[1] (p.Lys537fs) (rs863224829)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213843 SCV000277173 pathogenic Hereditary cancer-predisposing syndrome 2018-03-16 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 RCV000657535 SCV000779271 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing This deletion of four nucleotides in MSH6 is denoted c.1610_1613delAGTA at the cDNA level and p.Lys537IlefsX33 (K537IfsX33) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGTA[delAGTA]TCTT. The deletion causes a frameshift which changes a Lysine to an Isoleucine at codon 537, and creates a premature stop codon at position 33 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.1610_1613delAGTA, also defined as MSH6 c.1606_1609delAGTA using alternate nomenclature, has been reported in individuals with colon and pancreatic cancer (Siraj 2017, Dudley 2018). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000196707 SCV000695789 likely pathogenic Lynch syndrome 2017-01-31 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.1610_1613delAGTA (p.Lys537Ilefs) 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.1634_1637delAAGA, c.1637_1638delAG). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121328 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant was reported in a conference abstract (European Human Genetics Conference 2014) in a patient with multiple primary tumors between 21 and 27 years of age including two metachronous colorectal cancers, a fillodes tumour of the breast, a glioblastoma and a clear cell carcinoma of the ovaries who also carried MSH6 p.Arg1076His (not classified by LabCorp, VUS in ClinVar). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Invitae RCV000791395 SCV000255259 pathogenic Hereditary nonpolyposis colon cancer 2018-07-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys537Ilefs*33) 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 an individual undergoing multipanel genetic testing for Lynch syndrome (PMID: 28514183), and in individuals affected with colorectal and pancreatic cancer (PMID: 28975465, 29360161). This variant is also known as c.1606_1609delAGTA in the literature. ClinVar contains an entry for this variant (Variation ID: 216859). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657535 SCV000888244 pathogenic not provided 2018-04-24 criteria provided, single submitter clinical testing

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