The TP53 c.764T>A (p.Ile255Asn; p.I255N) variant has been observed in somatic cancers in COSMIC (COSV52714133, 23 occurrences) and has not been reported in ClinVar.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed allele frequency of 0, which is below the TP53 PM2_Supporting threshold of less than 0.00003.2 TP53 functional assay evidence supports loss of function, as the TP53 VCEP Functional-worksheet lists I255N as non-functional in Kato and loss-of-function in the other eligible assays shown, consistent with PS3.3 TP53 in silico evidence supports a damaging effect because the TP53 PP3/BP4 worksheet assigns c.764T>A (p.Ile255Asn) as PP3_moderate with BayesDel 0.347565, while SpliceAI predicts no significant splice impact (max delta score 0.00).4
Final classification
Likely Pathogenic
PS3PM2PP3
TP53
c.764T>A
p.Ile255Asn
This variant
The TP53 c.764T>A (p.Ile255Asn; p.I255N) variant has been observed in somatic cancers in COSMIC (COSV52714133, 23 occurrences) and has not been reported in ClinVar.
TP53 VCEP v2.4.0 Tavtigian point-based final classification framework: PS3_Strong (4) + PP3_Moderate (2) + PM2_Supporting (1) = 7 points, which is within the Likely Pathogenic range of 6-9 points.
Classification rationale
PS3PM2PP3
Likely Pathogenic
TP53 c.764T>A
PS3 + PM2 + PP3
→
Likely Pathogenic
1
cosmicclinvar ↗
3
vcep_f_u_n_c_t_i_o_n_a_l___w_o_r_k_s_h_e_e_tPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
4
vcep_p_p_3___b_p_4___c_o_d_e_sspliceai ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
PS3
Strong
review
Pathogenic
TP53 functional data support loss of function for p.(Ile255Asn). In the TP53 VCEP Functional-worksheet, I255N is listed as non-functional in Kato and as loss-of-function in the other eligible assays shown, which meets the TP53 PS3 strong rule.
Functional-worksheet row: I255N | NA | Non-functional | LOF | LOF | LOF | NA | PS3TP53 functional rule: non-functional on Kato and LOF by the majority of other eligible assays = PS3
PM2
Supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the TP53 PM2_Supporting threshold of less than 0.00003 overall and below 0.00004 within any ancestry group.
gnomAD v2.1: absentgnomAD v4.1: absent
PP3
Moderate
review
Pathogenic
TP53 in silico evidence supports a damaging effect for this missense variant. In the TP53 PP3/BP4 worksheet, c.764T>A (p.Ile255Asn) is assigned Class C65 with BayesDel 0.347565 and a precomputed code of PP3_moderate; SpliceAI shows no splice effect (max delta score 0.00).
PP3-BP4 worksheet row: c.764T>A | p.Ile255Asn | Class C65 | 0.347565 | PP3_moderateSpliceAI max delta score 0.00
Assessed · not applied
· 4 not met · 9 not assessed
Pathogenic
PS1
No previously established TP53 VCEP pathogenic or likely pathogenic variant causing the same amino acid change was identified in the available evidence, so PS1 cannot be determined from the current data.
PS2
No confirmed de novo data, parentage confirmation, or proband cancer-point information was identified, so PS2 cannot be applied.
PS4
This variant meets PM2_Supporting based on population data, but no germline Li-Fraumeni syndrome case observations or PS4 point-based evidence were identified, so PS4 cannot be scored.
PM1
This missense variant affects codon 255, which is not one of the predefined TP53 major hotspot codons (175, 245, 248, 249, 273, 282).
PM5
No TP53 VCEP-established pathogenic or likely pathogenic missense comparison variants at codon 255 were identified in the available evidence, so PM5 cannot be determined from the current data.
PP1
No segregation data were identified, so PP1 cannot be applied.
PP4
No blood variant allele fraction data or qualifying low-level mosaic observations were identified, so PP4 cannot be applied.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0, which is below the TP53 BA1 threshold of at least 0.001.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0, which is below the TP53 BS1 threshold of at least 0.0003.
BS2
No data were identified showing this variant in unrelated females aged at least 60 years without cancer from a single source, so BS2 cannot be applied.
BS3
Available functional evidence does not support normal TP53 protein function.
BS4
No data showing lack of segregation in affected family members were identified, so BS4 cannot be applied.
BP4
Available TP53 in silico evidence does not support a benign computational prediction.
N/A · 12
PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52714133, n = 23 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Understanding the function-structure and function-mutation relationships of p53
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
Strong
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
Strong
Mutational processes shape the landscape of TP53 mutations in human cancer.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
Strong
Sources & reference links