Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000546.3 | Alternative | 2640 nt | 252–1433 |
| NM_000546.5 | RefSeq Select | 2591 nt | 203–1384 |
| 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 I255N variant has been functionally characterized and demonstrated to be inactivating. In vivo studies with yeast and in vitro studies with human cancer cell lines have shown a loss of transactivational and growth suppression activities, respectively, compared to the wildtype. This evidence supports a damaging effect of the TP53 I255N mutation.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 140 bp |
| Donor Loss (DL) | 0.0 | 52 bp |
| Acceptor Gain (AG) | 0.0 | 44 bp |
| Donor Gain (DG) | 0.0 | -18 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: 'PVS1 applies to predicted loss-of-function variants (nonsense, frameshift, canonical ±1,2 splice sites) expected to undergo nonsense-mediated decay.' The evidence for this variant shows: it is a missense change (I255N) and not a predicted null variant. Therefore, this criterion is not applied at Not Applied strength because the variant type does not meet PVS1 specifications.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Strong: same amino acid change as a previously established Pathogenic variant via different nucleotide change.' The evidence for this variant shows: no other pathogenic variant at codon 255 is documented. Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic variant with the same amino acid change.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is based on de novo occurrence with points needed. The evidence for this variant shows: no confirmed de novo cases. Therefore, this criterion is not applied at Not Applied strength because there is no de novo inheritance data.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3_Strong is: 'Non-functional on Kato et al. data AND loss of function (LOF) on another assay (e.g., Giacomelli et al., Kotler et al., or another assay showing low function).' The evidence for this variant shows: the TP53 I255N variant was non-functional in a yeast transactivation assay consistent with Kato et al. and showed loss of growth suppression activity in human cancer cell lines. Therefore, this criterion is applied at Strong strength because the variant meets both Kato et al. non-functionality and additional LOF assay evidence.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Points-based system for multiple probands with LFS-associated cancers.' The evidence for this variant shows: no proband counts or case series reported. Therefore, this criterion is not applied at Not Applied strength because there is no case evidence.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: 'Moderate for missense variants within codons 175, 245, 248, 249, 273, or 282.' The evidence for this variant shows: I255N is outside these hotspot codons. Therefore, this criterion is not applied at Not Applied strength because it is not located in a defined hotspot.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2_Supporting is: 'This rule should be applied at supporting level if allele frequency <0.00003 in gnomAD.' The evidence for this variant shows: it is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant frequency meets the absent-from-controls requirement.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 applies to recessive conditions with trans configuration variants. The evidence for this variant shows: TP53 is not a recessive gene and no trans variant data are available. Therefore, this criterion is not applied at Not Applied strength.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 applies to protein length changes (in‐frame deletions/insertions). The evidence for this variant shows: it is a missense substitution without length change. Therefore, this criterion is not applied at Not Applied strength.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: 'Moderate for missense variants at a residue where ≥1 other pathogenic missense variant has been seen.' The evidence for this variant shows: no other pathogenic missense variant has been reported at codon 255. Therefore, this criterion is not applied at Not Applied strength.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 applies to assumed de novo occurrences without confirmation. The evidence for this variant shows: no de novo data reported. Therefore, this criterion is not applied at Not Applied strength.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: 'Supporting for segregation in 3–4 meioses; higher strengths for more.' The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied at Not Applied strength.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation and where missense is a common mechanism. The evidence for TP53 shows: numerous benign and pathogenic missense variants occur. Therefore, this criterion is not applied at Not Applied strength.
PP3 (Not Applied)
According to VCEP guidelines, PP3 applies when BayesDel ≥0.16 with splicing predictions. The evidence for this variant shows: in silico predictions are mixed and no consistent damaging BayesDel score. Therefore, this criterion is not applied at Not Applied strength.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 applies when patient phenotype is highly specific for a gene. The evidence for this variant shows: no clinical phenotype information provided. Therefore, this criterion is not applied at Not Applied strength.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 applies to reputable source assertions without primary data. The evidence for this variant shows: absent from ClinVar and no expert assertions. Therefore, this criterion is not applied at Not Applied strength.
BA1 (Not Applied)
According to VCEP guidelines, BA1 applies at ≥0.001 allele frequency in gnomAD. The evidence for this variant shows: allele frequency is 0. Therefore, this criterion is not applied at Not Applied strength.
BS1 (Not Applied)
According to VCEP guidelines, BS1 applies at allele frequency ≥0.0003 and <0.001 in gnomAD. The evidence for this variant shows: allele frequency is 0. Therefore, this criterion is not applied at Not Applied strength.
BS2 (Not Applied)
According to VCEP guidelines, BS2 applies for multiple unaffected older individuals. The evidence for this variant shows: no such data. Therefore, this criterion is not applied at Not Applied strength.
BS3 (Not Applied)
According to VCEP guidelines, BS3 requires functional assays showing no loss of function. The evidence for this variant shows: functional studies demonstrate loss of function. Therefore, this criterion is not applied at Not Applied strength.
BS4 (Not Applied)
According to VCEP guidelines, BS4 applies for lack of segregation in affected members. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 applies to missense in a gene where only truncating variants cause disease. The evidence for TP53 shows: missense is a common disease mechanism. Therefore, this criterion is not applied at Not Applied strength.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies when observed in trans with a pathogenic variant for a dominant disorder. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied at Not Applied strength.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame deletions in repetitive regions. The evidence for this variant shows: it is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4_Supporting is: 'Missense variants with BayesDel score <0.16 and > -0.008 irrespective of aGVGD score AND no predicted differences in splicing (SpliceAI < 0.2).' The evidence for this variant shows: SpliceAI predicts no impact on splicing and computational tools overall lean benign. Therefore, this criterion is applied at Supporting strength because the in silico evidence meets BP4 specifications.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternate molecular basis for disease. The evidence for this variant shows: no such context. Therefore, this criterion is not applied at Not Applied strength.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 applies to a variant with a benign assertion from a reputable source without evidence. The evidence for this variant shows: no such assertions. Therefore, this criterion is not applied at Not Applied strength.
BP7 (Not Applied)
According to VCEP guidelines, BP7 applies to synonymous or deep intronic variants with no splicing impact. The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied at Not Applied strength.