ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.378C>G (p.Tyr126Ter)

dbSNP: rs1567554500
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000702157 SCV000830998 likely pathogenic Li-Fraumeni syndrome 2018-06-14 criteria provided, single submitter clinical testing 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. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). 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. This variant has been observed in an individual affected with medulloblastoma (PMID: 24651015). This variant is not present in population databases (ExAC no frequency). 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.
Ambry Genetics RCV002343542 SCV002622593 pathogenic Hereditary cancer-predisposing syndrome 2021-12-20 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV003472237 SCV004204258 pathogenic Adrenocortical carcinoma, hereditary 2023-03-01 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV004026584 SCV004930551 pathogenic Li-Fraumeni syndrome 1 2024-02-13 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Laboratory for Genotyping Development, RIKEN RCV003165877 SCV002758172 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research
Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University RCV003999725 SCV004046831 likely pathogenic Adrenal cortex carcinoma no assertion criteria provided clinical testing

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