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
OpenThe p.Q144* pathogenic mutation (also known as c.430C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 430. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration was identified in an individual with a clinical diagnosis of Li-Fraumeni Syndrome (Morgan JE et al. Hum. Mutat. 2010 Apr; 31(4):484-91). 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 sequence change creates a premature translational stop signal (p.Gln144*) 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: 20127978). ClinVar contains an entry for this variant (Variation ID: 634688). For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The TP53 Q144* variant is a truncating mutation that results in the premature termination of the TP53 protein. Functional evidence indicates that truncating mutations in TP53 generally lead to the production of truncated protein forms that are inactivating. Experimental studies have shown that such mutations promote cancer cell proliferation, survival, and metastasis, partly due to aberrant protein localization affecting cell survival pathways. Although Q144* has not been biochemically characterized specifically, it is predicted to result in a loss of TP53 protein function 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) | 0.0 | -228 bp |
| Donor Loss (DL) | 0.01 | 154 bp |
| Acceptor Gain (AG) | 0.0 | -211 bp |
| Donor Gain (DG) | 0.02 | -328 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "PS1 Strong: same amino acid change as a previously established pathogenic variant but different nucleotide change." The evidence for this variant shows: Q144* is a nonsense change producing a premature stop codon, not a missense change at the same amino acid as another pathogenic variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "PS2 Very Strong: ≥8 points for confirmed de novo occurrences." The evidence for this variant shows: no confirmed de novo occurrence data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "PS3 should not be applied at any strength if PVS1 is applied at full strength." The evidence for this variant shows: PVS1 has been applied at Very Strong strength. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: point‐based proband/case‐control evidence (Very Strong ≥8 points, etc.). The evidence for this variant shows: no proband counts or case‐control data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Moderate: missense variants within codons 175, 245, 248, 249, 273, 282 or ≥10 somatic occurrences; Supporting: 2–9 somatic occurrences." The evidence for this variant shows: Q144* is a truncating variant outside of missense hotspot codons. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting: variant allele frequency <0.00003 in gnomAD or equivalent large database." The evidence for this variant shows: the allele frequency is 0% in gnomAD (0/251,276 alleles). Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: TP53‐associated disease is autosomal dominant and no trans allele data exist. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in‐frame indels or stop‐loss variants." The evidence for this variant shows: Q144* is a nonsense variant causing premature termination, not an in-frame indel or stop‐loss. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Strong: missense variant at a residue with ≥2 different pathogenic missense variants; Moderate/Supporting for fewer events." The evidence for this variant shows: Q144* is a nonsense change, not a missense variant. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Supporting: assumed de novo without confirmation of paternity/maternity." The evidence for this variant shows: no de novo assumption data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting: cosegregation in 3–4 meioses across one or more families." The evidence for this variant shows: no familial segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and common mechanism is missense." The evidence for this variant shows: Q144* is a truncating variant, not a missense change. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "PP3 should not be used in combination with PVS1." The evidence for this variant shows: PVS1 has been applied at Very Strong strength. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Moderate: phenotype highly specific to a single gene disorder; Supporting: observation in tumor VAF contexts." The evidence for this variant shows: no specific phenotype or VAF data. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence for independent evaluation." The evidence for this variant shows: ClinVar reports Q144* as Pathogenic from two clinical laboratories. Therefore, this criterion is applied at Supporting strength.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency ≥0.001 in any continental population database." The evidence for this variant shows: allele frequency is 0 in gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Filtering allele frequency ≥0.0003 but <0.001 in a continental population." The evidence for this variant shows: allele frequency is 0 in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong: ≥8 unrelated unaffected females ≥60 years without cancer in a single source." The evidence for this variant shows: no such unaffected elderly female data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong: functional assays show normal function on Kato et al. AND no LOF on another assay." The evidence for this variant shows: truncating mutations in TP53 result in loss of function. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong: lack of segregation in affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants cause disease." The evidence for this variant shows: Q144* is a truncating variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with pathogenic variant for dominant disorder or in cis with another pathogenic variant." The evidence for this variant shows: no such allele phase data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame deletions/insertions in repetitive region without known function." The evidence for this variant shows: nonsense variant, not an in‐frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Moderate: missense with BayesDel ≤–0.008 and no splicing impact OR Supporting for BayesDel <0.16 with no splicing impact." The evidence for this variant shows: Q144* is a nonsense change. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without evidence for independent review." The evidence for this variant shows: ClinVar reports pathogenic, not benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting: synonymous or intronic variant outside core splice motifs with no predicted splicing impact." The evidence for this variant shows: Q144* is a nonsense change in coding sequence. Therefore, this criterion is not applied.