ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3476dup (p.Tyr1159Ter) (rs587782111)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130627 SCV000185503 pathogenic Hereditary cancer-predisposing syndrome 2019-03-26 criteria provided, single submitter clinical testing The c.3476dupA pathogenic mutation (also known as p.Y1159*), located in coding exon 6 of the MSH6 gene, results from a duplication of A at nucleotide position 3476. This changes the amino acid from a tyrosine to a stop codon within coding exon 6. This alteration was identified in a patient diagnosed with early onset colon cancer (Latham A et al. J. Clin. Oncol., 2019 Feb;37:286-29). Two other alterations resulting in the same premature stop codon (c.3477C>A and c.3477delC) have been identified in multiple individuals suspected of having Lynch syndrome (Bonadona V et al. JAMA. 2011 Jun;305:2304-10; van Lier MG et al. J. Pathol. 2012 Apr;226:764-74). In addition to the clinical data presented in the literature, 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000607246 SCV000731759 pathogenic Lynch syndrome 2017-07-14 criteria provided, single submitter clinical testing The p.Tyr1159X (c.3476_3477insA) variant in MSH6 has not been previously reporte d in the literature, but has been reported in ClinVar by other clinical laborato ries (Variation ID# 141918). This variant was absent from large population studi es. This nonsense variant leads to a premature termination codon at position 115 9, which is predicted to lead to a truncated or absent protein. Heterozygous los s of function of the MSH6 gene is an established disease mechanism in Lynch synd rome. Another nonsense variant at an adjacent nucleotide position (c.3477C>A) th at results in the same amino acid change has been reported in two individuals wi th Lynch syndrome (Perez-Carbonell 2010 and Bonadona 2011). Microsatellite inst ability was documented in the individual reported (Perez-Carbonell 2010). In sum mary, this variant meets criteria to be classified as pathogenic for Lynch syndr ome in an autosomal dominant manner based upon the predicted impact to the prote in and absence from controls.
GeneDx RCV000202052 SCV000779579 pathogenic not provided 2021-03-12 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Chubb 2016, Espenschied 2017, Latham 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 30376427, 24755471, 28514183, 28152038, 28696559, 28502729, 27329137, 31447099, 32719484)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000607246 SCV000917756 pathogenic Lynch syndrome 2018-04-09 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3476dupA (p.Tyr1159X) 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. The variant was absent in 249448 control chromosomes (gnomAD and publications). The variant, c.3476dupA, has been reported in the literature in individuals affected with Lynch Syndrome (Chubb_2016, Espenschied_2017, Rey_2017). These data indicate that the variant may be associated with disease. In addition, the c.3477C>A and c.3477delC variants that cause the same nonsense change, p.Tyr1159X, have been reported in multiple affected individuals (Bonadona_2011, Marignol_2008, Perez-Cabonell_2011, Van Lier_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000819698 SCV000960374 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-01-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr1159*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 28514183, 27329137). ClinVar contains an entry for this variant (Variation ID: 141918). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000202052 SCV000257256 likely pathogenic not provided no assertion criteria provided research

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