ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1087C>T (p.Gln363Ter) (rs587783057)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410310 SCV000487361 pathogenic MYH-associated polyposis 2016-06-08 criteria provided, single submitter clinical testing
GeneDx RCV000413062 SCV000490628 pathogenic not provided 2018-08-06 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1171C>T at the cDNA level and p.Gln391Ter (Q391X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also reported as MUTYH Gln377Ter using an alternate reference sequence (NM_001048171.1), has been reported in the homozygous or compound heterozygous state in several individuals with multiple adenomatous polyps and/or colorectal cancer (Nielsen 2005, Aretz 2006, Croitoru 2007, Cleary 2009), and functional studies by Ali et. al. (2008) demonstrated severely defective glycosylase and DNA binding activities. Based on currently available evidence, we consider MUTYH Gln391Ter to be pathogenic.
Invitae RCV000410310 SCV000545766 pathogenic MYH-associated polyposis 2020-11-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 391 (p.Gln391*) of the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587783057, ExAC 0.002%). This variant has been reported in individuals affected with MUTYH-associated polyposis in the homozygous state or in combination with another pathogenic variant (PMID: 16140997, 19732775, 24444654). This variant is also known as c.1129C>T (p.Q377X) in the literature. ClinVar contains an entry for this variant (Variation ID: 156509). An experimental study has shown that this missense change disrupts MUTYH protein function and results in reduced glycosylase activity and DNA binding activity. (PMID: 18534194). Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000569738 SCV000670131 pathogenic Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing The p.Q391* pathogenic mutation (also known as c.1171C>T), located in coding exon 12 of the MUTYH gene, results from a C to T substitution at nucleotide position 1171. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration, also referred to as Q377X, has been previously described in several individuals with attenuated polyposis and/or colon cancer in homozygous state or in conjugation with another pathogenic mutation (Nielsen M et al. J. Med. Genet. 2005 42(9):e54; Croitoru M et al. J. Surg. Oncol. 2007; 95(6):499-506; Olschwang S et al. Genet. Test. 2007; 11(3):315-20; Jones N et al. Gastroenterology 2009; 137(2):489-94, 494.e1; Vogt S et al. Gastroenterology 2009; 137(6):1976-85.e1-10; Ricci MT et al. J. Hum. Genet., 2017 Feb;62:309-315). 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.
Color Health, Inc RCV000569738 SCV000685548 pathogenic Hereditary cancer-predisposing syndrome 2020-02-18 criteria provided, single submitter clinical testing
Mendelics RCV000410310 SCV000837752 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000413062 SCV000888297 pathogenic not provided 2017-11-24 criteria provided, single submitter clinical testing
Pathway Genomics RCV000144635 SCV000189962 pathogenic Carcinoma of colon 2014-07-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000144635 SCV001553370 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Gln391X variant was identified in 4 of 1188 proband chromosomes (frequency: 0.003) from individuals or families with colorectal cancer (Jones 2009, Vogt 2009, Win 2011). The variant was also identified in dbSNP (ID: rs587783057) as With Pathogenic allele, ClinVar (classified as pathogenic by Counsyl, GeneDx, Invitae, Pathway Genomics), Clinvitae (classified as pathogenic by ClinVar, Invitae (alias c.1129C>T)), UMD-LSDB (22X causal), Insight Colon Cancer Gene Variant Database (classified as probably pathogenic), databases. The variant was not identified in Genesight-COGR, databases. The variant was identified in control databases in 4 of 245576 chromosomes at a frequency of 0.000016 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include EuropeanNon-Finnish in 4 of 111460 chromosomes (freq: 0.000036), while the variant was not observed in the African, Other, Latino, AshkenaziJewish, EastAsian, EuropeanFinnish, and SouthAsian populations. The c.1171C>T variant leads to a premature stop codon at position 391 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis 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.
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001572626 SCV001792255 pathogenic Breast carcinoma 2021-08-19 no assertion criteria provided clinical testing Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000413062 SCV001799792 pathogenic not provided no assertion criteria provided clinical testing

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