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"This variant has been reported in ClinVar as Likely benign (1 clinical laboratories) and as Uncertain significance (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.16 | 88 bp |
| Donor Loss (DL) | 0.14 | -28 bp |
| Acceptor Gain (AG) | 0.0 | -28 bp |
| Donor Gain (DG) | 0.0 | 281 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines for PVS1: 'PVS1 applies to canonical splice variants (±1,2 positions) or null variants leading to NMD in TP53.' The variant is located at +284 intronic position, outside the canonical splice site. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines for PS1: 'Applies to variants with same amino acid change as established pathogenic variant.' This variant is non-coding and does not result in an amino acid change. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to VCEP guidelines for PS2: 'Requires confirmed de novo occurrence with parental testing.' No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines for PS3: 'Requires non-functional or loss-of-function evidence from validated TP53 assays.' No functional studies have been performed. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines for PS4: 'Requires case-control or proband point totals for LFS cancers.' No such case data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines for PM1: 'Applies to hotspot missense codons in DNA-binding domain.' This variant is intronic and not a missense change at a hotspot codon. Therefore, PM1 is not applied.
PM2 (Not Applied)
According to VCEP guidelines for PM2_Supporting: 'Variant allele frequency must be <0.00003 overall and <0.00004 in any ancestry group.' Although the overall MAF is 0.0000185 (<0.00003), the African/African-American subpopulation frequency is 0.0000502 (>0.00004). Therefore, PM2 is not applied.
PM3 (Not Applied)
According to standard ACMG guidelines for PM3: 'Applies to variants observed in trans with a pathogenic variant in a recessive disorder.' TP53-related conditions are dominant and no trans data exist. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines for PM4: 'Applies to protein length changes such as in-frame indels.' This variant is intronic with no protein length change. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines for PM5: 'Applies to missense changes at residues with other pathogenic missense variants.' This variant is intronic. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to VCEP guidelines for 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 for PP1: 'Requires segregation data in multiple meioses.' No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines for PP2: 'Applies to missense variants in genes with low rate of benign missense.' This variant is intronic. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines for PP3: 'Requires multiple lines of computational evidence supporting a deleterious effect.' SpliceAI score is 0.16 (below typical splicing impact threshold) and no other in silico tool predicts deleteriousness. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to VCEP guidelines for PP4: 'Requires specific TP53-related phenotype observations.' No phenotype data are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines for PP5: 'Applies to assertions from reputable sources without supporting evidence.' ClinVar submissions are conflicting (Likely benign and VUS). Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines for BA1: 'Requires filtering allele frequency ≥0.001 in any gnomAD ancestry group.' The highest subpopulation MAF is 0.0000502, below the BA1 threshold. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines for BS1: 'Requires FAF ≥0.0003 but <0.001 in a gnomAD ancestry group.' The highest subpopulation MAF is 0.0000502, below 0.0003. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines for BS2: 'Requires ≥2 unrelated older unaffected individuals.' No such data are available. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines for BS3: 'Requires functional assays demonstrating no loss of function in TP53.' No functional assay data are available. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines for BS4: 'Requires lack of segregation in affected family members.' No segregation data are available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines for BP1: 'Applies to missense variant in a gene where only truncating variants cause disease.' This variant is intronic. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines for BP2: 'Applies to observed in trans with pathogenic for dominant disorder.' Not applicable for this TP53 variant. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines for BP3: 'Applies to in-frame indels in repetitive regions.' This variant is intronic, not an indel. Therefore, BP3 is not applied.
BP4 (Supporting)
According to standard ACMG guidelines for BP4: 'Multiple lines of computational evidence suggest no impact on gene or gene product.' SpliceAI predicts no splicing impact (max score 0.16) and other tools show no deleterious effect. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to standard ACMG guidelines for BP5: 'Applies when variant found in cis with a pathogenic variant.' No cis observations exist. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines for BP6: 'Applies to assertions from reputable sources without evidence.' ClinVar submissions are conflicting. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines for BP7: 'Applies to intronic variants outside ±1,2 with SpliceAI ≤0.1.' SpliceAI = 0.16, above the BP7 cutoff. Therefore, BP7 is not applied.