About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.764T>A, p.(Ile255Asn)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen TP53 VCEP v2.4.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Strong
PS3 · strong
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.
PM2Supporting
PM2 · supporting
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.
PP3Moderate
PP3 · moderate
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).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
Cancer Hotspots ↗
For specialists
Technical detail
ACMG/AMP criteria under ClinGen TP53 VCEP v2.4.0, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 4 not met · 9 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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).
No criteria match.
Met · 3
PS3 StrongTP53 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. Details ▾Hide ▴
Rule
Non-functional on Kato et al. data AND loss of function by the majority of other eligible assays.
Evidence considered
- Functional-worksheet row: I255N | NA | Non-functional | LOF | LOF | LOF | NA | PS3
- TP53 functional rule: non-functional on Kato and LOF by the majority of other eligible assays = PS3
Sources
vcep_f_u_n_c_t_i_o_n_a_l___w_o_r_k_s_h_e_e_tvcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___f_u_n_c_t_i_o_n_a_l___r_u_l_e___c_o_d_e_sPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗128266092997996530224644
PM2 SupportingThis 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. Details ▾Hide ▴
Rule
Apply at Supporting when allele frequency is <0.00003 overall and <0.00004 within any non-founder ancestry group.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
Sources
PP3 ModerateTP53 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). Details ▾Hide ▴
Rule
Missense variant with aGVGD Class C65 and BayesDel score ≥0.16.
Evidence considered
- PP3-BP4 worksheet row: c.764T>A | p.Ile255Asn | Class C65 | 0.347565 | PP3_moderate
- SpliceAI max delta score 0.00
Sources
vcep_p_p_3___b_p_4___c_o_d_e_svcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___p_p_3___2_c___b_p_4___2_c___a_n_d___b_p_7spliceai ↗
Not met · 4 · evaluated, threshold not reached
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. Details ▾Hide ▴
Rule
BA1 requires filtering allele frequency ≥0.001 in a qualifying ancestry group.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
Sources
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. Details ▾Hide ▴
Rule
BS1 requires filtering allele frequency ≥0.0003 and <0.001 in a qualifying ancestry group.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
Sources
BS3 Available functional evidence does not support normal TP53 protein function. The TP53 VCEP Functional-worksheet lists I255N as non-functional in Kato and loss-of-function in the other eligible assays shown, which argues against BS3. Details ▾Hide ▴
Rule
BS3 requires functional or partially functional protein activity without evidence of LOF under TP53 VCEP rules.
Evidence considered
- Functional-worksheet row: I255N | NA | Non-functional | LOF | LOF | LOF | NA | PS3
Sources
vcep_f_u_n_c_t_i_o_n_a_l___w_o_r_k_s_h_e_e_tvcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___f_u_n_c_t_i_o_n_a_l___r_u_l_e___c_o_d_e_sPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗128266092997996530224644
BP4 Available TP53 in silico evidence does not support a benign computational prediction. The TP53 PP3/BP4 worksheet assigns c.764T>A (p.Ile255Asn) a BayesDel score of 0.347565 with a precomputed code of PP3_moderate, and SpliceAI shows no splice effect (max delta score 0.00), so BP4 is not met. Details ▾Hide ▴
Rule
BP4 requires a benign BayesDel category with no predicted splicing impact.
Evidence considered
- PP3-BP4 worksheet row: c.764T>A | p.Ile255Asn | Class C65 | 0.347565 | PP3_moderate
- SpliceAI max delta score 0.00
Sources
vcep_p_p_3___b_p_4___c_o_d_e_sspliceai ↗vcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___p_p_3___2_c___b_p_4___2_c___a_n_d___b_p_7
Not assessed · 9 · no assessment recorded
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. Details ▾Hide ▴
Rule
TP53 PS1 requires the same amino acid change as a previously established TP53 VCEP pathogenic or likely pathogenic variant with no relevant splice difference.
Evidence considered
- ClinVar has no entry for this variant
- No TP53 VCEP comparison variant for the same amino acid change was provided in the available records
Still missing
- A TP53 VCEP-curated comparison variant with the same amino acid change was not identified in the available sources.
Sources
PS2 No confirmed de novo data, parentage confirmation, or proband cancer-point information was identified, so PS2 cannot be applied. Details ▾Hide ▴
Rule
TP53 PS2 requires de novo evidence with point-based scoring.
Evidence considered
- No de novo observations were reported
Still missing
- No de novo testing data were identified.
- No TP53 PS2 point tally could be calculated from the available evidence.
Sources
vcep_t_a_b_l_e___o_f___l_f_s___c_a_n_c_e_r_s___a_n_d___p_o_i_n_t_s___f_o_r___p_s_2___a_n_d___p_p_1___c_o_d_e___a_p_p_l_i_c_a_t_i_o_n
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. Details ▾Hide ▴
Rule
TP53 PS4 requires PM2_Supporting first and then case-point scoring in affected individuals.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- No germline case-point data identified
Still missing
- No proband-level TP53/Li-Fraumeni syndrome observations were identified for PS4 point calculation.
Sources
PM1 This missense variant affects codon 255, which is not one of the predefined TP53 major hotspot codons (175, 245, 248, 249, 273, 282). Cancer Hotspots review for p.(Ile255Asn) was flagged as uncertain, so the same-amino-acid-change occurrence threshold needed for TP53 PM1 could not be confirmed from the available evidence. Details ▾Hide ▴
Rule
TP53 PM1 can be applied for specified hotspot codons or for the same amino acid change with sufficient Cancer Hotspots somatic occurrences.
Evidence considered
- Codon 255 is not in the predefined TP53 hotspot codon list
- Cancer Hotspots result for I255N was marked uncertain and needs human review
Still missing
- Cancer Hotspots exact amino acid change occurrence for p.(Ile255Asn) requires confirmation.
Sources
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. Details ▾Hide ▴
Rule
TP53 PM5 requires a different missense variant at the same residue previously classified as pathogenic or likely pathogenic under TP53 VCEP rules.
Evidence considered
- No residue-matched TP53 VCEP comparison variant was identified in the available records
- ClinVar has no entry for this variant
Still missing
- A TP53 VCEP-curated pathogenic or likely pathogenic missense variant at residue 255 was not identified in the available sources.
Sources
PP1 No segregation data were identified, so PP1 cannot be applied. Details ▾Hide ▴
Rule
TP53 PP1 requires cosegregation across informative meioses.
Evidence considered
- No cosegregation observations were reported
Still missing
- No informative family segregation data were identified.
Sources
vcep_t_a_b_l_e___o_f___l_f_s___c_a_n_c_e_r_s___a_n_d___p_o_i_n_t_s___f_o_r___p_s_2___a_n_d___p_p_1___c_o_d_e___a_p_p_l_i_c_a_t_i_o_n
PP4 No blood variant allele fraction data or qualifying low-level mosaic observations were identified, so PP4 cannot be applied. Details ▾Hide ▴
Rule
TP53 PP4 requires low-VAF constitutional mosaic observations within specified ranges.
Evidence considered
- No VAF data reported
Still missing
- No variant allele fraction data were identified.
- No qualifying TP53 mosaic observation data were identified.
Sources
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. Details ▾Hide ▴
Rule
TP53 BS2 requires unaffected older female carriers from a single source.
Evidence considered
- No BS2-eligible unaffected observations reported
Still missing
- No eligible unaffected older female observations from a single source were identified.
Sources
BS4 No data showing lack of segregation in affected family members were identified, so BS4 cannot be applied. Details ▾Hide ▴
Rule
TP53 BS4 requires lack of segregation in affected relatives.
Evidence considered
- No family non-segregation observations were reported
Still missing
- No informative non-segregation data were identified.
Sources
vcep_t_a_b_l_e___o_f___l_f_s___c_a_n_c_e_r_s___a_n_d___p_o_i_n_t_s___f_o_r___p_s_2___a_n_d___p_p_1___c_o_d_e___a_p_p_l_i_c_a_t_i_o_n
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense change, p.(Ile255Asn), and is not a null, canonical splice-site, frameshift, nonsense, initiation-codon, or exon-level loss-of-function variant. SpliceAI shows no predicted splice effect (max delta score 0.00), so the TP53 PVS1 framework is not applicable. Details ▾Hide ▴
Rule
TP53 PVS1 flowchart applies to null variants and certain splice variants, not missense variants without a splice effect.
Evidence considered
- NM_000546.5:c.764T>A encodes TP53 p.(Ile255Asn)
- SpliceAI max delta score 0.00
Sources
spliceai ↗vcep_p_v_s_1___f_l_o_w_c_h_a_r_t
PM3 N/APM3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
PM4 N/APM4 is not used in the TP53 VCEP framework. Details ▾Hide ▴
PM6 N/APM6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
PP2 N/APP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
PP5 N/APP5 is not used in the TP53 VCEP framework. Details ▾Hide ▴
BP1 N/ABP1 is not used in the TP53 VCEP framework. Details ▾Hide ▴
BP2 N/ABP2 is not used in the TP53 VCEP framework. Details ▾Hide ▴
BP3 N/ABP3 is not used in the TP53 VCEP framework. Details ▾Hide ▴
BP5 N/ABP5 is not used in the TP53 VCEP framework. Details ▾Hide ▴
BP6 N/ABP6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or qualifying intronic variants. This variant is a missense change, so BP7 is not applicable. Details ▾Hide ▴
Rule
TP53 BP7 is limited to synonymous or qualifying intronic variants.
Evidence considered
- Variant consequence: missense, p.(Ile255Asn)
- SpliceAI max delta score 0.00
Sources
spliceai ↗vcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___p_p_3___2_c___b_p_4___2_c___a_n_d___b_p_7
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.5
- Coding (HGVS c.)
- NM_000546.5:c.764T>A
- Protein (HGVS p.)
- NP_000537.3:p.(Ile255Asn)
- GRCh38
- chr17:7674199 A>T
- GRCh37
- chr17:7577517 A>T
Gene diagram
Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.5. Select a row to find it on the plot.
TP53NM_000546.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TP53
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 ModerateTP53 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). Details ▾Hide ▴
Rule
Missense variant with aGVGD Class C65 and BayesDel score ≥0.16.
Evidence considered
- PP3-BP4 worksheet row: c.764T>A | p.Ile255Asn | Class C65 | 0.347565 | PP3_moderate
- SpliceAI max delta score 0.00
Sources
vcep_p_p_3___b_p_4___c_o_d_e_svcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___p_p_3___2_c___b_p_4___2_c___a_n_d___b_p_7spliceai ↗
BP4 Available TP53 in silico evidence does not support a benign computational prediction. The TP53 PP3/BP4 worksheet assigns c.764T>A (p.Ile255Asn) a BayesDel score of 0.347565 with a precomputed code of PP3_moderate, and SpliceAI shows no splice effect (max delta score 0.00), so BP4 is not met. Details ▾Hide ▴
Rule
BP4 requires a benign BayesDel category with no predicted splicing impact.
Evidence considered
- PP3-BP4 worksheet row: c.764T>A | p.Ile255Asn | Class C65 | 0.347565 | PP3_moderate
- SpliceAI max delta score 0.00
Sources
vcep_p_p_3___b_p_4___c_o_d_e_sspliceai ↗vcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___p_p_3___2_c___b_p_4___2_c___a_n_d___b_p_7
BP7 N/ABP7 applies to synonymous or qualifying intronic variants. This variant is a missense change, so BP7 is not applicable. Details ▾Hide ▴
Rule
TP53 BP7 is limited to synonymous or qualifying intronic variants.
Evidence considered
- Variant consequence: missense, p.(Ile255Asn)
- SpliceAI max delta score 0.00
Sources
spliceai ↗vcep_f_l_o_w_c_h_a_r_t___f_o_r___a_p_p_l_i_c_a_t_i_o_n___o_f___p_p_3___2_c___b_p_4___2_c___a_n_d___b_p_7
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637581
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000546.5%3Ac.764T%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7577517-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7674199-A-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.764T…
- OncoKB ↗www.oncokb.org/gene/TP53/I255N
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52714133, n = 23 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.