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. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with medulloblastoma or rhabdomyosarcoma (PMID: 24651015, 34308104). ClinVar contains an entry for this variant (Variation ID: 578988). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (PMID: 28961258). 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.

The p.Y126* pathogenic mutation (also known as c.378C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 378. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. This mutation was previously identified in the germline of one individual diagnosed with medulloblastoma (Kool M, Cancer Cell 2014 Mar; 25(3):393-405). This variant was also reported to be the result of a de novo mutation in an individual diagnosed with with a Wilms' tumor at 2 years of age and a medulloblastoma at 7 years of age (Renaux-Petel M et al. J Med Genet, 2018 03;55:173-180). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site; however direct evidence is insufficient at this time (Ambry internal data). An RNA study performed in cell lines identified two transcripts associated with this variant; one was predicted to introduce a stop codon at p.Y126 (p.Y126*) and the other was predicted to remove the amino acid at p.Y126 (p.Y126del). Functional studies performed with the resulting predicted proteins showed that the p.Y126del could induce p21 expression and apoptosis at levels comparable to the wild-type protein, while the p.Y126* could not (Makarov EM et al. PLoS One, 2017 Sep;12:e0185126). However, the clinical significance of this functional study is uncertain. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.