Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 2591 nt | 203–1384 |
| NM_000546.3 | Alternative | 2640 nt | 252–1433 |
| NM_000546.6 | MANE Select | 2512 nt | 143–1324 |
| NM_000546.4 | Alternative | 2586 nt | 198–1379 |
| NM_000546.2 | Alternative | 2629 nt | 252–1433 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis sequence change creates a premature translational stop signal (p.Tyr103*) 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 clinical features of Li-Fraumeni syndrome (PMID: 28681140). ClinVar contains an entry for this variant (Variation ID: 822878). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The TP53 Y103* variant is a truncating mutation that results in a premature stop codon, leading to the production of a truncated protein. Functional evidence indicates that truncating mutations in TP53 generally result in loss of protein function, promoting cancer cell proliferation, survival, and metastasis. Although Y103* has not been specifically biochemically characterized, it is predicted to be inactivating based on the effects of similar truncating mutations.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.07 | 8 bp |
| Donor Loss (DL) | 0.01 | -66 bp |
| Acceptor Gain (AG) | 0.0 | -1 bp |
| Donor Gain (DG) | 0.08 | 134 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines: "Nonsense or frameshift variants predicted to undergo NMD (upstream of p.Lys351) apply PVS1 at Very Strong strength." The NM_000546.6:c.309C>G (p.Y103*) variant introduces a premature stop codon at amino acid 103, well upstream of p.Lys351, predicted to undergo NMD. Therefore, this criterion is applied at Very Strong strength.
PS1 (Not Applied)
According to VCEP guidelines: PS1 applies to variants resulting in the same amino acid change as a previously established TP53 pathogenic variant. The p.Y103* variant is a novel truncating change, not a reversion to a known pathogenic amino acid substitution. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines: PS2 applies when confirmed de novo with parental testing. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP caveat: "PS3 should not be applied at any strength if PVS1 is applied at full strength." PVS1 has been applied at Very Strong strength. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines: PS4 requires statistically increased prevalence of variant in affected individuals. No case–control or proband point data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines: PM1 applies to germline missense variants at defined DNA-binding domain hotspots. p.Y103* is a truncating variant, not missense. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines: "PM2_Supporting: allele frequency <0.00003 in gnomAD or other large database." The variant is absent from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG: PM3 applies to recessive disorders with trans observations. TP53 disorders are dominant and no trans data exist. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG: PM4 applies to protein length changes in in-frame indels or stop-loss. This is a stop-gain variant. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines: PM5 applies to missense variants at residues with other pathogenic missense changes. p.Y103* is truncating, not missense. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to VCEP guidelines: PM6 applies to assumed de novo without confirmation. No de novo information is available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines: PP1 applies when cosegregation is observed in families. No segregation data are provided. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG: PP2 applies for missense in genes with low benign missense rate. p.Y103* is a truncating variant. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP caveat: "PP3 should not be used in combination with PVS1." PVS1 is applied at full strength. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines: PP4 applies when a specific phenotype is highly predictive for a gene. No phenotype data are provided. Therefore, PP4 is not applied.
PP5 (Supporting)
According to standard ACMG: "PP5: Reputable source recently reports variant as pathogenic, but the evidence is not available for independent evaluation." ClinVar lists this variant as Pathogenic by five laboratories. Therefore, PP5 is applied at Supporting strength.
BA1 (Not Applied)
According to VCEP guidelines: BA1 requires allele frequency ≥0.001. The variant is absent in population databases. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines: BS1 applies for filtering AF ≥0.0003 but <0.001. The variant is absent. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines: BS2 requires ≥8 unaffected older females. No such data. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines: BS3 applies when functional assays show no loss of function. No such data. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines: BS4 applies with lack of segregation in affected family members. No data available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG: BP1 applies to missense in gene where only truncating variants cause disease. p.Y103* is truncating, so BP1 is not applicable. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG: BP2 applies when in trans with a pathogenic variant in dominant disorders. Not applicable. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG: BP3 applies to in-frame indels in repetitive regions. Not applicable. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines: BP4 applies to missense or splice predictions. p.Y103* is a stop-gain, so BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG: BP5 applies when variant found in a case with an alternate molecular basis. No such data. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG: BP6 applies to reputable source reporting benign without evidence. Not relevant. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines: BP7 applies to silent or intronic variants with no splice impact. p.Y103* is coding nonsense. Therefore, BP7 is not applied.