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

gnomAD frequency: 0.00001  dbSNP: rs865954220

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223135	SCV000274525	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-21	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 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	Familial adenomatous polyposis 2	2023-08-23	criteria provided, single submitter	clinical testing	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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 230848). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change affects the initiator methionine of the MUTYH mRNA. The next in-frame methionine is located at codon 15.
Color Diagnostics, LLC DBA Color Health	RCV000223135	SCV001359413	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	This variant causes the loss of the translation initiation codon in the MUTYH protein. However, codon 15 encodes methionine, which may serve as an alternative translation initiation site. In addition, two other transcripts use different downstream initiation codons. 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.
GeneDx	RCV001770172	SCV002001230	uncertain significance	not provided	2020-12-11	criteria provided, single submitter	clinical testing	Initiator codon variant in a gene for which a downstream in-frame ATG produces an alternate clinically-relevant isoform that may result in a functional protein (Plotz 2012); Has not been previously published as pathogenic or benign to our knowledge; Observed in 3/280214 (0.0011%) alleles in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 22473953)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002282055	SCV002570193	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003165560	SCV002758527	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research