ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1571dup (p.Tyr524Ter) (rs1553412966)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000504411 SCV000592590 pathogenic Lynch syndrome 2014-08-21 criteria provided, single submitter clinical testing
Invitae RCV000538459 SCV000624662 pathogenic Hereditary nonpolyposis colon cancer 2017-05-22 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 4 of the MSH6 mRNA (c.1571dupA), causing a frameshift at codon 524. This creates a premature translational stop signal (p.Tyr524*) 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 hereditary non-polyposis colorectal cancer (PMID: 24100870). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000657809 SCV000779564 pathogenic not provided 2017-01-24 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted MSH6 c.1571dupA at the cDNA level and p.Tyr524Ter (Y524X) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACTT[dupA]CAGT. The duplication creates a nonsense variant, which changes a Tyrosine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.1571dupA has been reported in an individual diagnosed with synchronous rectal and endometrial cancers; the rectal tumor was microsatellite instability-high (MSI-H) and demonstrated loss of MSH6 protein expression (Terui 2013). This variant was also observed in at least one individual undergoing multigene cancer panel testing due to a personal history of a Lynch syndrome-associated cancer and/or polyps, as well as one individual with a personal history of a sarcoma (Yurgelun 2015, Ballinger 2016). This variant is considered pathogenic.

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