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 P72Rfs*51 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. These alterations have been experimentally shown to promote cancer cell proliferation, survival, and metastasis, partly due to aberrant mitochondrial localization and regulation of survival-related genes. Therefore, the TP53 P72Rfs*51 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) | 0.0 | 100 bp |
| Donor Loss (DL) | 0.05 | 41 bp |
| Acceptor Gain (AG) | 0.01 | -85 bp |
| Donor Gain (DG) | 0.01 | -159 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines for PVS1: "Nonsense or frameshift variants predicted to result in nonsense-mediated decay (NMD) for nonsense variants upstream of p.Lys351 and for frameshift induced premature termination codon (PTC) upstream of p.Lys351: PVS1 (Very Strong Strength)". The evidence for this variant shows: the c.215_216delCCinsG (P72Rfs*51) creates a frameshift resulting in a premature stop codon upstream of p.Lys351, predicted to trigger NMD. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP conditions for NMD upstream of p.Lys351.
PS1 (Not Applied)
According to VCEP guidelines for PS1: "Can be applied to variants asserted as Pathogenic or Likely Pathogenic following TP53 VCEP’s specifications" for missense variants. The evidence for this variant shows: c.215_216delCCinsG is a frameshift, not a missense. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines for PS2: point system based on confirmed de novo events. The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines caveat: "PS3 should not be applied at any strength if PVS1 is applied at full strength." The evidence for this variant shows: PVS1_Very Strong has been applied. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines for PS4: "Increased prevalence in affected individuals over controls" with a point system. The evidence for this variant shows: no case-control or proband point data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines for PM1: "Missense variants within hotspot codons". The evidence for this variant shows: it is a frameshift variant, not missense. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines for PM2: "This rule should be applied at supporting level. Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD”. The evidence for this variant shows: absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant’s frequency is below the threshold.
PM3 (Not Applied)
According to standard ACMG guidelines for PM3: "For variants in trans with a pathogenic variant in recessive disorders". The evidence for this variant shows: not evaluated in a recessive context. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines for PM4: "Protein length changes due to in-frame indels or stop-loss variants". The evidence for this variant shows: it is a frameshift predicted to cause NMD, covered by PVS1. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines for PM5: "Missense variant at an amino acid residue where pathogenic missense changes were seen". The evidence for this variant shows: it is a frameshift, not missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines for PM6: "Assumed de novo without confirmation of paternity/maternity". The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines for PP1: "Cosegregation in families". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines for PP2: "Missense variant in a gene with low rate of benign missense variants". The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines caveat: "PP3 should not be used in combination with PVS1." The evidence for this variant shows: PVS1 applied. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines for PP4: "Phenotype specificity". The evidence for this variant shows: no phenotype specificity data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines for PP5: "Reputable source reports variant as pathogenic". The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines for BA1: "Stand-alone benign filtering allele frequency ≥0.001". The evidence for this variant shows: absent in population. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines for BS1: "Filtering allele frequency ≥0.0003 but <0.001". The evidence for this variant shows: absent in population. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines for BS2: "Observation in ≥8 unaffected older females". The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines for BS3: "Functional data shows no loss of function". The evidence for this variant shows: truncating predicted LOF and PVS1 applied. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines for BS4: "Lack of segregation in affected members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines for BP1: "Missense variant in gene where only LOF causes disease". The evidence for this variant shows: it is a LOF variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines for BP2: "Observed in trans with a pathogenic variant for a dominant disorder". The evidence for this variant shows: not applicable. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines for BP3: "In-frame indels in repetitive region without functional impact". The evidence for this variant shows: frameshift variant. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines for BP4: "Computational evidence supports benign effect". The evidence for this variant shows: truncating variant, PVS1 applied. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines for BP5: "Variant found in case with an alternate cause". The evidence for this variant shows: no data. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines for BP6: "Reputable source reports variant as benign". The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines for BP7: "Synonymous or intronic variant with no splicing impact". The evidence for this variant shows: not applicable (frameshift). Therefore, this criterion is not applied.