ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.970C>T (p.Gln324Ter) (rs587780082)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212713 SCV000149662 pathogenic not provided 2018-11-27 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.1012C>T at the cDNA level and p.Gln338Ter (Q338X) 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 known as c.970C>T (p.Gln324Ter) and c.928C>T (p.Gln310Ter) using alternate transcripts, has been reported in the compound heterozygous state in several individuals with autosomal recessive MUTYH-Associated Polyposis (Sampson 2003, Aretz 2006, Bouguen 2007, Cattaneo 2008, Vogt 2009). In addition, a functional study demonstrated that this variant is associated with severely defective DNA glyosylase activity (Goto 2010). We therefore consider this variant to be pathogenic.
Ambry Genetics RCV000115753 SCV000216400 pathogenic Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing The p.Q338* pathogenic mutation (also known as c.1012C>T), located in coding exon 12 of the MUTYH gene, results from a C to T substitution at nucleotide position 1012. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration has been described in several individuals with attenuated polyposis and/or colon cancer (Sampson JR et al. Lancet. 2003 Jul;362:39-41; Aretz S et al. Int. J. Cancer. 2006 Aug;119:807-14; Olschwang S et al. Genet. Test. 2007;11:315-20; Bouguen G et al. Dis. Colon Rectum. 2007 Oct;50:1612-7; Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6; Jones N et al. Gastroenterology. 2009 Aug;137:489-94, 494.e1; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85.e1-10; Guarinos C et al. Clin. Cancer Res. 2014 Mar;20:1158-68). The glycosylation function of the p.Q338* mutant MUTYH was classified as extremely impaired in one study measuring DNA glycosylase activity on adenine mispaired with 8-hydroxyguanine (Goto M et al. Hum. Mutat. 2010 Nov;31:E1861-74). Of note, p.Q338* has also been referred to as p.Q324X and p.Q310* in the literature. 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.
Invitae RCV000465024 SCV000545804 pathogenic MYH-associated polyposis 2020-10-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln338*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587780082, ExAC 0.1%). This variant has been observed in individuals affected with MUTYH-associated polyposis (MAP) (PMID: 12853198, 2084865, 19732775, 16557584, 24470512). This variant is also known as Q310X and Q324X in the literature. ClinVar contains an entry for this variant (Variation ID: 127835). Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 20663686, 18534194). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000115753 SCV000685534 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000465024 SCV000700131 pathogenic MYH-associated polyposis 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 53 year old male diagnosed with colon cancer at age 47. Patient is compound heterozygous for a second pathogenic variant in MUTYH. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
PreventionGenetics,PreventionGenetics RCV000212713 SCV000806334 pathogenic not provided 2016-12-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000465024 SCV001361132 pathogenic MYH-associated polyposis 2019-07-10 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1012C>T (p.Gln338X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.2e-05 in 232530 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (8.2e-05 vs 0.0046), allowing no conclusion about variant significance. c.1012C>T has been reported in the literature in multiple individuals affected with MUTYH-associated Polyposis (Sampson_2003, Vogt_2009, Ricci_2017). These data indicate that the variant is very likely to be associated with disease. A functional study, GOTO_2010 reports the variant severely impairs adenine DNA glycosylase activity. Six ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212713 SCV001500819 pathogenic not provided 2021-01-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212713 SCV000592706 pathogenic not provided no assertion criteria provided clinical testing

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