ClinVar Miner

Submissions for variant NM_025077.4(TOE1):c.2T>C (p.Met1Thr)

dbSNP: rs1646823787
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001066037 SCV001231030 uncertain significance Familial adenomatous polyposis 2 2019-03-22 criteria provided, single submitter clinical testing 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. This variant has not been reported in the literature in individuals with MUTYH-related conditions. This variant is not present in population databases (ExAC no frequency). 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 RCV001188722 SCV001355856 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-06 criteria provided, single submitter clinical testing This variant results in the loss of the translation initiator methionine at codon 1 of the MUTYH gene. However, downstream methionines, including Met15, are used in naturally occurring transcripts. These transcripts lack the mitochondrial localization signal (MLS) at residues 1-14, but the clinical impact is not well understood (PMID: 20725929). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MUTYH-related disorders in the literature. This variant has not been identified 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.

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