ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.378C>G (p.Tyr126Ter) (rs1567554500)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000702157 SCV000830998 likely pathogenic Li-Fraumeni syndrome 2018-06-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr126*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with medulloblastoma (PMID: 24651015). An experimental study in cell lines has shown that this sequence change generates a cryptic acceptor splice site, the use of which creates a transcript that skips the premature termination codon and encodes a protein with a single amino acid deletion, p53ΔY126. This protein is nearly as active as the wild-type protein in inducing p21 expression and apoptosis (PMID: 28961258). However, the frequency of the use of this cryptic splice site in vivo is not known, therefore the clinical significance of this finding is uncertain. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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