ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.2647_2651del (p.Lys883fs) (rs587782712)

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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 RCV000132188 SCV000187268 pathogenic Hereditary cancer-predisposing syndrome 2019-01-24 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000200490 SCV000255261 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-21 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides from exon 4 of the MSH6 mRNA (c.3037_3041delAAGAA), causing a frameshift at codon 1013. This creates a premature translational stop signal (p.Lys1013Valfs*3) 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 the literature in an individual affected with Lynch syndrome (PMID: 27064304). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000202303 SCV000565221 pathogenic not provided 2017-05-31 criteria provided, single submitter clinical testing This deletion of 5 nucleotides in MSH6 is denoted c.3037_3041delAAGAA at the cDNA level and p.Lys1013ValfsX3 (K1013VfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TGAA[delAAGAA]GTTG. The deletion causes a frameshift which changes a Lysine to a Valine at codon 1013, and creates a premature stop codon at position 3 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.3037_3041delAAGAA has been observed in at least one individual with Lynch syndrome, and in another with a family history of colon cancer (Foley 2015, Sjursen 2016). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202303 SCV000601555 pathogenic not provided 2017-03-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781590 SCV000919756 pathogenic Lynch syndrome 2018-09-04 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3037_3041delAAGAA (p.Lys1013ValfsX3) 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 (e.g., c.3052_3053delCT, p.Leu1018fsX4; c.3103C>T, p.Arg1035X; c.3155_3156delAG, p.Glu1052fsX13). The variant was absent in 215278 control chromosomes (gnomAD). The variant, c.3037_3041delAAGAA, has been reported in the literature in several individuals affected with Lynch Syndrome or with a history of colon cancer (Foley_2015, Morak_2017, Sjursen_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color RCV000132188 SCV001359871 pathogenic Hereditary cancer-predisposing syndrome 2020-02-04 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202303 SCV000257232 likely pathogenic not provided no assertion criteria provided clinical testing

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