ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.267G>A (p.Trp89Ter) (rs748170941)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164326 SCV000214957 pathogenic Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing The p.W103* pathogenic mutation (also known as c.309G>A), located in coding exon 3 of the MUTYH gene, results from a G to A substitution at nucleotide position 309. This changes the amino acid from a tryptophan to a stop codon within coding exon 3. This mutation was reported in conjunction with an MUTYH founder mutation in an Australian woman with early-onset adenomatous polyposis (Kairupan CF et al. Int. J. Cancer 2005 Aug;116:73-7). 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 RCV000196257 SCV000253865 pathogenic MYH-associated polyposis 2020-08-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp103*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs748170941, ExAC 0.001%). This variant has been reported as co-occurring with a pathogenic variant (p.Gly396Asp, also known as G382D) in MUTYH in an individual with adenomatous polyposis (PMID: 15761860). This variant is also known as G267A (W89X) in the literature. ClinVar contains an entry for this variant (Variation ID: 184976). Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000523882 SCV000617565 pathogenic not provided 2018-02-21 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.309G>A at the cDNA level, p.Trp103Ter (W103X) at theprotein level, and results in the change of a Tryptophan to Nonsense (TGG>TGA). This variant, also published asMUTYH c.267G>A (p.W89X) using alternate nomenclature, has been observed in at least one individual with a historyof polyposis who was also found to harbor a known pathogenic MUTYH variant (Kairupan 2005). MUTYH Trp103Terwas not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The1000 Genomes Consortium 2015, Lek 2016). Based on currently available evidence, we consider this variant to bepathogenic. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenicvariants on opposite chromosomes in MUTYH.
Counsyl RCV000196257 SCV000678197 likely pathogenic MYH-associated polyposis 2017-03-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164326 SCV000690556 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000523882 SCV000888311 pathogenic not provided 2017-11-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000196257 SCV000915418 uncertain significance MYH-associated polyposis 2018-08-15 criteria provided, single submitter clinical testing The MUYTH c.267G>A (p.Trp89Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Trp89Ter variant has been reported in at least one study in which it is found in one patient in a compound heterozygous state with a second known pathogenic missense variant (Kairupan et al. 2005). The female proband was reported to have more than 50 polyps at 34 years of age, but no colorectal cancer or other types of cancer at the time of study (Kairupan et al. 2005). Control data are unavailable for this variant which is reported at a frequency of 0.000015 in the European (non-Finnish) population of the Exome Aggregation Consortium, however this is based on a single allele and the variant is presumed to be rare. Based on the available evidence and potential impact of stop-gained variants, the p.Trp89Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for MYH-associated polyposis.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000196257 SCV000993569 pathogenic MYH-associated polyposis 2018-12-10 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000196257 SCV001448571 pathogenic MYH-associated polyposis 2020-11-27 criteria provided, single submitter clinical testing Variant summary: MUTYH c.309G>A (p.Trp103X) 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 4e-06 in 251488 control chromosomes (gnomAD). c.309G>A has been reported in the literature in at least one individual affected with MUTYH-Associated Polyposis (Kairupan_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000523882 SCV000592677 pathogenic not provided no assertion criteria provided clinical testing The MUTYH p.Trp103* variant was identified in 1 of 364 proband chromosomes (frequency: 0.003) from individuals or families with adenomatous polyposis (Kairupan 2005). The individual identified in this study was a compound heterozygote with a second pathogenic MUTYH mutation, p.Gly382Asp.The variant was also identified in dbSNP (ID: rs748170941) as "With Pathogenic allele ", ClinVar (classified as pathogenic by Invitae, Ambry Genetics and three other submitters; as likely pathogenic by Counsyl), and in the COGR database. The variant was not identified in Cosmic, or UMD-LSDB. The variant was identified in control databases in 1 of 246268 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European in 1 of 111716 chromosomes (freq: 0.000009), but not in other populations. The p.Trp103* variant leads to a premature stop codon at position 103, 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.

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.