TP53 c.787_795delinsCATCTACT, p.Asn263HisfsTer82
NM_000546.6:c.787_795delinsCATCTACT
Pathogenic
The TP53 N263Hfs*82 frameshift variant introduces a premature stop upstream of p.Lys351, meeting PVS1 at Very Strong and PM2 at Supporting. No additional criteria apply, leading to a Likely Pathogenic classification per ACMG/AMP and TP53 VCEP guidelines.
ACMG/AMP Criteria Applied
PVS1
PM2
Genetic Information
Gene & Transcript Details
Gene
TP53
Transcript
NM_000546.6
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 11 exons | Reverse |
| NM_000546.3 | Alternative | 11 exons | Reverse |
| NM_000546.4 | Alternative | 11 exons | Reverse |
| NM_000546.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_000546.6:c.787_795delinsCATCTACT
Protein Change
N263Hfs*82
Location
Exon 8
(Exon 8 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 263 in gene TP53
Variant interpretation based on transcript NM_000546.6
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HGVS InputNM_000546:c.787_795delinsCATCTACT
Active Tracks
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
4180
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (4180 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 263 in gene TP53
Functional Summary
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.
Database Previews
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
PS3 (Not Applied) Strength Modified
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
PS4 (Not Applied) Strength Modified
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
PM1 (Not Applied) Strength Modified
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
PM2 (Supporting) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
PM4 (Not Applied) Strength Modified
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
PM5 (Not Applied) Strength Modified
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
PM6 (Not Applied) Strength Modified
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
PP1 (Not Applied) Strength Modified
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
PP2 (Not Applied) Strength Modified
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
PP3 (Not Applied) Strength Modified
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
PP4 (Not Applied) Strength Modified
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
PP5 (Not Applied) Strength Modified
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
BA1 (Not Applied) Strength Modified
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
BS1 (Not Applied) Strength Modified
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
BS2 (Not Applied) Strength Modified
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
BS3 (Not Applied) Strength Modified
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
BS4 (Not Applied) Strength Modified
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
BP1 (Not Applied) Strength Modified
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
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
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
BP4 (Not Applied) Strength Modified
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
BP7 (Not Applied) Strength Modified
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.