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.
ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Pathogenic/Likely pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 3
- First in ClinVar:
- Oct 10, 2018
- Most recent Submission:
- Apr 15, 2023
- Last evaluated:
- Dec 20, 2021
- Accession:
- VCV000578988.23
- Variation ID:
- 578988
- Description:
- single nucleotide variant
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NM_000546.6(TP53):c.378C>G (p.Tyr126Ter)
- Allele ID
- 574637
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 17p13.1
- Genomic location
- 17: 7675234 (GRCh38) GRCh38 UCSC
- 17: 7578552 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.378C>G MANE Select NP_000537.3:p.Tyr126Ter nonsense NM_001126112.3:c.378C>G NP_001119584.1:p.Tyr126Ter nonsense NM_001126113.3:c.378C>G NP_001119585.1:p.Tyr126Ter nonsense NM_001126114.3:c.378C>G NP_001119586.1:p.Tyr126Ter nonsense NM_001126115.2:c.-19C>G 5 prime UTR NM_001126116.2:c.-19C>G 5 prime UTR NM_001126117.2:c.-19C>G 5 prime UTR NM_001126118.2:c.261C>G NP_001119590.1:p.Tyr87Ter nonsense NM_001276695.3:c.261C>G NP_001263624.1:p.Tyr87Ter nonsense NM_001276696.3:c.261C>G NP_001263625.1:p.Tyr87Ter nonsense NM_001276697.3:c.-100C>G 5 prime UTR NM_001276698.3:c.-100C>G 5 prime UTR NM_001276699.3:c.-100C>G 5 prime UTR NM_001276760.3:c.261C>G NP_001263689.1:p.Tyr87Ter nonsense NM_001276761.3:c.261C>G NP_001263690.1:p.Tyr87Ter nonsense NC_000017.11:g.7675234G>C NC_000017.10:g.7578552G>C NG_017013.2:g.17317C>G LRG_321:g.17317C>G LRG_321t1:c.378C>G LRG_321p1:p.Tyr126Ter - Protein change
- Y126*, Y87*
- Other names
- -
- Canonical SPDI
- NC_000017.11:7675233:G:C
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- dbSNP: rs1567554500
- VarSome
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Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Likely pathogenic | 1 | criteria provided, single submitter | Aug 12, 2021 | RCV000702157.5 | |
| Pathogenic | 1 | criteria provided, single submitter | Dec 20, 2021 | RCV002343542.1 | |
| Pathogenic | 1 | no assertion criteria provided | Jul 1, 2021 | RCV003165877.1 |
Help
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation | Variation viewer | Related variants | ||
|---|---|---|---|---|---|---|
| HI score Help | TS score Help | Within gene | All | |||
| TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2836 | 2931 | |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(Dec 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002622593.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Aug 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000830998.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023 |
Comment:
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 … (more)
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 (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with medulloblastoma (PMID: 24651015). Studies have shown that this premature translational stop signal does not affect mRNA 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. (less)
|
|
|
Pathogenic
(Jul 01, 2021)
|
no assertion criteria provided
Method: research
|
Gastric cancer
Affected status: unknown
Allele origin:
germline
|
Laboratory for Genotyping Development, RIKEN
Accession: SCV002758172.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
|
Functional evidence
Help| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
| Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome. | Renaux-Petel M | Journal of medical genetics | 2018 | PMID: 29070607 |
| The rare nonsense mutation in p53 triggers alternative splicing to produce a protein capable of inducing apoptosis. | Makarov EM | PloS one | 2017 | PMID: 28961258 |
| Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. | Nykamp K | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28492532 |
| Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. | Kool M | Cancer cell | 2014 | PMID: 24651015 |
| TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. | Ruijs MW | Journal of medical genetics | 2010 | PMID: 20522432 |
Text-mined citations for rs1567554500...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Apr 15, 2023