ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.1240C>T (p.Gln414Ter) (rs766420907)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465367 SCV000545718 pathogenic MYH-associated polyposis 2020-01-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln414*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs766420907, ExAC 0.05%). This variant has been observed in an individual affected with polyposis and colorectal cancer (PMID: 27705013). ClinVar contains an entry for this variant (Variation ID: 406824). Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000773657 SCV000907352 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000773657 SCV001170737 pathogenic Hereditary cancer-predisposing syndrome 2019-04-12 criteria provided, single submitter clinical testing The p.Q414* pathogenic mutation (also known as c.1240C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1240. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This alteration was reported with another MUTYH gene mutation in a woman diagnosed with adenomatous colon polyposis (15-30 polyps) and colon cancer diagnosed at age 63 (Marabelli M et al. Genet Test Mol Biomarkers 2016 12;20:777-785). 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000465367 SCV000592713 pathogenic MYH-associated polyposis no assertion criteria provided clinical testing The MUTYH p.Gln414X variant was not identified in the literature nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, COSMIC, MutDB, “Zhejiang Colon Cancer Database”, or ClinVar database. The variant was identified in UMD (5X, but is unvalidated), and in the “InSiGHT Colon Cancer Database”. The p.Gln414X variant leads to a premature stop codon at position 414, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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