ClinVar Miner

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

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Total submissions: 8
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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 The c.3037_3041delAAGAA pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a deletion of five nucleotides at positions 3037 to 3041, causing a translational frameshift with a predicted alternate stop codon (p.K1013Vfs*3). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000200490 SCV000255261 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-08-08 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Health, Inc RCV000132188 SCV001359871 pathogenic Hereditary cancer-predisposing syndrome 2020-02-04 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202303 SCV000257232 likely pathogenic not provided no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355368 SCV001550240 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Lys1013ValfsX3 variant was identified in 2 of 1192 proband chromosomes (frequency: 0.002) from individuals or families with Lynch Syndrome and colon cancer (Foley 2015, Sjursen 2016). The variant was also identified in the following databases: dbSNP (ID: rs587782712) as "With Pathogenic allele", ClinVar (4x pathogenic, 1x likely pathogenic), Clinvitae (2x pathogenic), and Insight Hereditary Tumors Database. The variant was not identified in Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, or Mismatch Repair Genes Variant Database. The variant was also identified by our laboratory in one individual with Lynch Syndrome. The variant was not found in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3037_3041delAAGAA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1013 and leads to a premature stop codon at position 1015. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch Syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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