ClinVar Miner

Submissions for variant NM_012222.2(MUTYH):c.1092dup (p.Arg365fs) (rs768130289)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165254 SCV000215970 pathogenic Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing The c.1101dupC pathogenic mutation, located in coding exon 12 of the MUTYH gene, results from a duplication of C at nucleotide position 1101, causing a translational frameshift with a predicted alternate stop codon (p.R368Qfs*164). This alteration has been detected in conjunction with another MUTYH mutation in patients diagnosed with colorectal cancer and/or polyps (Lejeune S. et al. Hum Mutat. 2006 Oct;27(10):1064; Castillejo A et al. Eur J Cancer. 2014 Sep;50(13):2241-50). This alteration as also been detected as monoallelic in patients diagnosed with breast or ovarian cancer (Bonache S et al. J Cancer Res Clin Oncol. 2018 Oct 10). This variant is designated as 1059dupC in published 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.
GeneDx RCV000485059 SCV000568580 likely pathogenic not provided 2017-01-04 criteria provided, single submitter clinical testing This duplication of one nucleotide in MUTYH is denoted c.1101dupC at the cDNA level and p.Arg368GlnfsX164 (R368QfsX164) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GCCCCC[dupC]AGGG. The duplication causes a frameshift which changes an Arginine to a Glutamine at codon 368, and creates a premature stop codon at position 164 of the new reading frame. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 182 amino acids are no longer translated correctly and are replaced by 163 incorrect ones. This variant is predicted to cause loss of normal protein function through protein truncation. MUTYH Arg368GlnfsX164 has been reported in the compound heterozygous state with a pathogenic MUTYH variant in an individual with colorectal and breast cancer (Castillejo 2014). Based on the currently available information, we consider this duplication to be a likely pathogenic variant.
Invitae RCV000688652 SCV000816274 pathogenic MYH-associated polyposis 2020-10-09 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MUTYH gene (p.Arg368Glnfs*164). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 182 amino acids of the MUTYH protein. This variant is present in population databases (rs768130289, ExAC 0.009%). This variant has been reported in an individual affected with attenuated familial adenomatous polyposis (PMID: 16941501). Additionally, this variant has been reported in an individual affected with colon and breast cancer (PMID: 24953332). This variant is also known as c.1059dupC (Arg354Glnfs*164) in the literature. ClinVar contains an entry for this variant (Variation ID: 185770). This frameshift disrupts the conserved PCNA binding motif of MUTYH (Gln526-Phe533, also known as Gln512-Phe519 in the literature because of transcript nomenclature differences), which has been shown to be critical for MUTYH-PCNA binding (PMID: 11092888, 26377631). Experimental studies have shown that MUTYH and PCNA co-localize at sites of DNA replication, and that MUTYH-PCNA complexes possess adenine glycosylase activity (PMID: 11433026). In MUTYH-deficient murine cells, a mutated MUTYH protein in which the conserved PCNA binding motif was disrupted did not increase repair efficiency as compared to wild-type MUTYH (PMID: 11864576). In addition, a different truncation (exon 15-16 deletion) that deletes the final 2 exons of the MUTYH gene has been determined to be pathogenic (PMID: 17949294, 25820570). This further suggests that disruption of this region of the MUTYH protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000165254 SCV000905857 pathogenic Hereditary cancer-predisposing syndrome 2020-03-23 criteria provided, single submitter clinical testing

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.