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
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The TP53 N263Hfs*82 variant is a truncating mutation in the TP53 gene, a critical tumor suppressor involved in the DNA damage response pathway. Functional evidence indicates that truncating mutations in TP53 lead to the production of C-terminally truncated proteins, which are predicted to be inactivating. Experimental studies have shown that these truncated proteins can promote cancer cell proliferation, survival, and metastasis, partly due to their aberrant localization to the mitochondria and regulation of genes involved in cell survival. Therefore, the TP53 N263Hfs*82 variant is functionally characterized as likely damaging.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.15 | 15 bp |
| Donor Loss (DL) | 0.0 | 66 bp |
| Acceptor Gain (AG) | 0.0 | -12 bp |
| Donor Gain (DG) | 0.0 | -18 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: 'PVS1 applies to frameshift variants with premature termination codon upstream of p.Lys351 predicted to undergo NMD.' The evidence for this variant shows: N263Hfs*82 introduces a frameshift with a PTC upstream of p.Lys351, predicted to undergo NMD. Therefore, this criterion is applied at Very Strong strength because the variant meets the VCEP PVS1 decision tree for NMD-inducing frameshifts.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant gives PS1.' The evidence shows: this variant is a frameshift, not a missense change identical to any known pathogenic allele. Therefore, this criterion is not applied because no identical amino acid change has been reported as pathogenic.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'Very Strong: ≥8 points for confirmed de novo events; Strong: 4–7 points; Moderate: 2–3 points; Supporting: 1 point.' The evidence shows: no de novo inheritance data are available. Therefore, this criterion is not applied because de novo status is unconfirmed.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: 'PS3 should not be applied if PVS1 is applied at full strength.' The evidence shows: PVS1 has been applied at full strength. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Proband counts equating to point thresholds for case-level data.' The evidence shows: no probands or case-control data are reported. Therefore, this criterion is not applied because no case counts are available.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: 'Moderate for missense variants within hotspot codons 175, 245, 248, 249, 273, or 282.' The evidence shows: this variant is a frameshift at codon 263, not a missense at those hotspot residues. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'PM2_Supporting applies when allele frequency is <0.00003 in gnomAD.' The evidence shows: the variant is absent from gnomAD. Therefore, this criterion is applied at Supporting strength because the allele frequency meets VCEP PM2 thresholds.
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 shows: no recessive context or in trans data are available. 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 in non-repetitive regions.' The evidence shows: this is a frameshift predicted to undergo NMD, already captured by PVS1. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: 'Missense variant at a residue with ≥1 different pathogenic missense variant.' The evidence shows: this variant is a frameshift, not a missense change at a residue with known pathogenic missense variants. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: 'Unconfirmed de novo with no parental confirmation.' The evidence shows: no de novo or parental testing data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: 'Supporting for segregation in 3–4 meioses across one or more families.' The evidence shows: no familial segregation data are 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.' The evidence shows: variant is a frameshift, not a missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: 'Computational evidence (e.g., BayesDel ≥0.16, SpliceAI ≥0.2) for deleterious effect.' The evidence shows: this is a frameshift and no relevant computational scores for missense or splicing impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: 'Phenotype specificity with at least 2 independent observations of the variant with VAF 5–25%.' The evidence shows: no phenotype or VAF data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic.' The evidence shows: no ClinVar or other reputable pathogenic assertion is available. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Filtering allele frequency ≥0.001 in a gnomAD subpopulation.' The evidence shows: the variant is absent from gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Filtering allele frequency ≥0.0003 but <0.001 in a gnomAD subpopulation.' The evidence shows: the variant is absent from gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Observation in ≥8 unaffected older females without cancer.' The evidence shows: no such observations are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Strong functional evidence of no loss of function.' The evidence shows: this variant is a truncating LOF allele. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: 'Lack of segregation in affected family members.' The evidence 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 LOF is disease mechanism.' The evidence shows: this is a LOF 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 a dominant disorder or in cis with another variant.' The evidence shows: no phasing data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions in repetitive regions without known function.' The evidence shows: this is a frameshift, not in-frame. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Computational evidence predicts no impact (BayesDel <0.16, SpliceAI <0.2).' The evidence shows: variant is a frameshift with no relevant computational scores. 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 shows: no such cases are 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.' The evidence shows: no benign assertions are available. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Synonymous or intronic variant with no splicing impact.' The evidence shows: this is a frameshift variant. Therefore, this criterion is not applied.