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
TP53
Final classification
Likely Pathogenic
TP53 c.764T>A · p.Ile255Asn
TP53
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 ↗
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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 supports · met
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Mutational processes shape the landscape of TP53 mutations in human cancer.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links