ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1612dup (p.Tyr538fs)

gnomAD frequency: 0.00001  dbSNP: rs1230092559
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000773949 SCV000907649 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing This variant inserts 1 nucleotide in exon 4 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics RCV000773949 SCV002705766 pathogenic Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing The c.1612dupT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of T at nucleotide position 1612, causing a translational frameshift with a predicted alternate stop codon (p.Y538Lfs*4). 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.
Myriad Genetics, Inc. RCV003453599 SCV004187101 pathogenic Lynch syndrome 5 2023-08-15 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355603 SCV001550534 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Tyr538LeufsX4 variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, MMR Gene Unclassified Variants Database, or Insight Hereditary Tumors Database. The variant was not identified 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 p. Tyr538LeufsX4 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 538 and leads to a premature stop codon at position 541. 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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