ClinVar Miner

Submissions for variant NM_025077.4(TOE1):c.1A>G (p.Met1Val) (rs865954220)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223135 SCV000274525 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-19 criteria provided, single submitter clinical testing The p.M1? variant (also known as c.2T>C), located in coding exon 1 of the MUTYH gene, results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. However, the MUTYH gene contains two alternate initiation sites located at codon 15 and 54 producing the beta and gamma isoforms of the protein (Parker AR, Cell. Mol. Life Sci. 2003 Oct; 60(10):2064-83.). These isoforms have been shown to be expressed in a wide variety of tissue types, although at lower levels than the M1-alpha isoform, and lacking the mitochondrial localization signal located in the first 14 amino acids (Plotz G, Hum. Mutat. 2012 Jul; 33(7):1067-74).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6501 samples (13002 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 200000 alleles tested) in our clinical cohort.This amino acid position is well conserved in available vertebrate species.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae RCV000687399 SCV000814963 uncertain significance MYH-associated polyposis 2019-06-04 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the MUTYH mRNA. The next in-frame methionine is located at codon 15. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 230848). This variant at the initiator codon is expected to affect translation initiation. However, there are alternative transcripts using downstream Met15 as an initiator codon that can potentially re-initiate the translation. Rescue of the translation may result in the N-terminal truncation missing mitochondrial localization signal (MLS) (residues 1-14), but the role of MLS is not well understood (PMID: 20725929). Therefore, it is uncertain whether this variant results in an absent or disrupted protein product. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000223135 SCV001359413 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-04 criteria provided, single submitter clinical testing This variant causes the loss of the translation initiation codon in the MUTYH protein. However, codon 15 codes for a methionine that may serve as an alternative translation initiation codon. In addition, two other alternative first exons encode alternative initiation codons. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/280214 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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.