ClinVar Miner

Submissions for variant NM_025077.4(TOE1):c.-39C>T (rs876658588)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217740 SCV000274037 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-04 criteria provided, single submitter clinical testing The c.36+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 1 in the MUTYH gene. 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 6503 samples (13006 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 nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Another alteration at this nucleotide position, c.36+5G>C (also known as IVS1+5G>C), has been shown to have approximately 30% translational efficiency compared to wild type in a lung cancer cell line (Yamaguchi S et al. Genes Cells. 2002 May;7(5):461-74). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507237 SCV000601648 uncertain significance not specified 2016-08-05 criteria provided, single submitter clinical testing
Invitae RCV001064196 SCV001229079 uncertain significance MYH-associated polyposis 2020-04-09 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the MUTYH gene. It does not directly change the encoded amino acid sequence of the MUTYH protein, but it affects a nucleotide within the consensus splice site of the intron. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 230475). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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