ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1815_1816del (p.Lys606fs) (rs1060502886)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000470844 SCV000551078 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-04-23 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 4 of the MSH6 mRNA (c.1815_1816delTA), causing a frameshift at codon 606. This creates a premature translational stop signal (p.Lys606Asnfs*33) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic. This particular variant has been reported in an individual affected with colorectal cancer (PMID: 26485756) and in a family affected with Lynch syndrome (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840013). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000486089 SCV000569502 pathogenic not provided 2016-06-29 criteria provided, single submitter clinical testing This deletion of two nucleotides in MSH6 is denoted c.1815_1816delTA at the cDNA level and p.Lys606AsnfsX33 (K606NfsX33) at the protein level. The normal sequence, with the bases that are deleted in braces, is AAAC[TA]AAAC. The deletion causes a frameshift which changes a Lysine to an Asparagine at codon 606, 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.1815_1816delTA, also denoted MSH6 c.1815delTA using alternative nomenclature, has been observed at least once, in an individual with colorectal cancer who met Bethesda Guidelines (Maccaroni 2015). We consider this variant to be pathogenic.
Ambry Genetics RCV000491721 SCV000580086 pathogenic Hereditary cancer-predisposing syndrome 2016-07-28 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000491721 SCV001352054 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001199932 SCV001370717 pathogenic Hereditary nonpolyposis colon cancer 2020-05-12 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1815_1816delTA (p.Lys606AsnfsX33) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 250498 control chromosomes (gnomAD). c.1815_1816delTA has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) associated tumors, and one of the probands was also noted to meet the Amsterdam II criteria for late onset HNPCC (Irmejs_2003, Maccaroni_2015, Waszak_2018). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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