ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.270C>A (p.Tyr90Ter) (rs121908380)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163049 SCV000213540 pathogenic Hereditary cancer-predisposing syndrome 2018-11-05 criteria provided, single submitter clinical testing The p.Y104* pathogenic mutation (also known as c.312C>A), located in coding exon 3 of the MUTYH gene, results from a C to A substitution at nucleotide position 312. This changes the amino acid from a tyrosine to a stop codon within exon 3. This alteration has been detected in the homozygous state in multiple colorectal polyposis families and has been shown to abolish normal MUTYH protein functions (Jones S et al. Hum. Mol. Genet. 2002 Nov;11:2961-7; Ali M et al. Gastroenterology. 2008 Aug;135:499-507; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85). In one study, the p.Y104* pathogenic mutation was reported in the homozygous state in one Italian individual diagnosed with MUTYH-associated polyposis (MAP) and in the compound heterozygous state in five other Italian MAP patients (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.
Invitae RCV000005617 SCV000218794 pathogenic MYH-associated polyposis 2020-10-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr104*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant has been observed in an individual affected with colorectal cancer (PMID: 24444654) and as homozygous in several individuals affected with MUTYH-associated polyposis syndrome (PMID: 12393807, 19732775). This variant is also known as p.Tyr90* in the literature. ClinVar contains an entry for this variant (Variation ID: 5296). Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000005617 SCV000487327 pathogenic MYH-associated polyposis 2015-12-22 criteria provided, single submitter clinical testing
GeneDx RCV000486820 SCV000567387 pathogenic not provided 2017-08-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.312C>A at the cDNA level and p.Tyr104Ter (Y104X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously reported as MUTYH c.270C>A or Y90X using alternate nomenclature, has been reported in the homozygous or compound heterozygous state with another pathogenic MUTYH variant in several individuals with adenomatous polyposis and/or colorectal cancer (Jones 2002, Croitoru 2004, Gismondi 2004, Croitoru 2007, Cattaneo 2007). Functional studies have demonstrated that this variant abrogates glycosylase and DNA binding activities (Ali 2008). Based on currently available evidence, we consider this variant to be pathogenic.
Color Health, Inc RCV000163049 SCV000685609 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000661934 SCV000784260 pathogenic Familial colorectal cancer 2018-03-05 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000005617 SCV000784261 pathogenic MYH-associated polyposis 2018-03-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000005617 SCV000919790 pathogenic MYH-associated polyposis 2017-11-24 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.312C>A (p.Tyr104X) variant results in a premature termination codon, predicted to cause a truncated or absent MUTYH 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 (e.g. c.1147delC, p.Ala385fsX23; c.1227_1228dupGG, p.Glu410fsX43). One in silico tool predicts a damaging outcome for this variant. This variant was found in 31/277196 control chromosomes at a frequency of 0.0001118, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state, and has been shown to be completely devoid of both glycosylase and DNA binding activities (Ali_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486820 SCV001134474 pathogenic not provided 2019-01-20 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in multiple symptomatic patients, and found in general population data that is consistent with pathogenicity. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.
OMIM RCV000005617 SCV000025799 pathogenic MYH-associated polyposis 2002-11-01 no assertion criteria provided literature only
GeneReviews RCV000005617 SCV000246163 pathogenic MYH-associated polyposis 2019-10-08 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353649 SCV000592679 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Tyr104X variant was identified in 12 of 622 proband chromosomes (frequency 0.019) from individuals or families with adenomatous polyposis and/or colorectal cancer (Croitoru 2007, Di Gregorio 2006, Jenkins 2006, O'Shea 2008, Ponti 2007, Vogt 2009). Two probands from these studies were identified as homozoygous carriers of the variant, while the remaining probands were compound heterozyous carriers of the variant with a second MUTYH variant. The variant was listed in dbSNP (ID: rs121908380) “With pathogenic allele” with a minor allele frequency of 0.001 (1000 Genomes Project), and was also identified in the HGMD, UMD (1X as a causal variant), and the “InSiGHT Colon Cancer Database”. The p.Tyr104X variant leads to a premature stop codon at position 104, 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. One functional study demonstrated an absence of both glycosylase and DNA binding activities for the variant (Ali 2008). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.