TP53 c.764T>A, p.Ile255Asn
NM_000546.5:c.764T>A
COSMIC ID: COSM11244, COSM437491
Likely Pathogenic
This legacy system is being phased out as Project HERA V3 is rolled out.
ACMG/AMP Criteria Applied
PS3
PM2
BP4
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_000546.3 | Alternative | 11 exons | Reverse |
| NM_000546.5 | RefSeq Select | 11 exons | Reverse |
| NM_000546.4 | Alternative | 11 exons | Reverse |
| NM_000546.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_000546.5:c.764T>A
Protein Change
I255N
Location
Exon 7
(Exon 7 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 255 in gene TP53
Alternate Identifiers
COSM11244, COSM437491
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.764T>A
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
COSMIC ID
COSM11244, COSM437491
Recurrence
23 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
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Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 255 in gene TP53
Functional Summary
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.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 4.81primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
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
PS4 (Not Applied) Strength Modified
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
PM1 (Not Applied) Strength Modified
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
PM2 (Supporting) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
PM4 (Not Applied) Strength Modified
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
PM5 (Not Applied) Strength Modified
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
PM6 (Not Applied) Strength Modified
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
PP1 (Not Applied) Strength Modified
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
PP2 (Not Applied) Strength Modified
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
PP3 (Not Applied) Strength Modified
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
PP4 (Not Applied) Strength Modified
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
PP5 (Not Applied) Strength Modified
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
BA1 (Not Applied) Strength Modified
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
BS1 (Not Applied) Strength Modified
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
BS2 (Not Applied) Strength Modified
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
BS3 (Not Applied) Strength Modified
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
BS4 (Not Applied) Strength Modified
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
BP1 (Not Applied) Strength Modified
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
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
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
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
BP7 (Not Applied) Strength Modified
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.