About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.761T>C, p.(Ile254Thr)
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Strong
PS3 · strong
In TP53 functional datasets curated by the TP53 VCEP, p.I254T was non-functional in the Kato assay and showed loss of function in the Funk, Giacomelli, and Kotler assays. This pattern is consistent with a damaging loss-of-function effect and meets TP53 PS3 at strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0 and therefore below the TP53 PM2 threshold of less than 0.00003 (0.003%). PM2 is met at supporting strength.
PP3Moderate
PP3 · moderate
For this missense variant, the TP53 VCEP bioinformatic worksheet assigns PP3_moderate. The BayesDel score is 0.598199, which is above the TP53 pathogenic threshold of 0.16, REVEL is high at 0.954, and SpliceAI predicts no significant splice effect (max delta score 0.00), supporting a damaging missense interpretation rather than a splicing explanation.
PP5Supporting
PP5 · supporting
Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + PP3 moderate (+2) + PP5 supporting (+1) = 8 points, which maps to Likely Pathogenic.
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.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
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
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: 4 met · 5 not met · 9 not assessed · 10 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.761T>C (p.Ile254Thr) variant has been observed in somatic cancers 9 times in COSMIC and has been reported in ClinVar, including a pathogenic expert panel assertion.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the TP53 PM2 threshold of less than 0.00003.
In TP53 functional studies curated by the TP53 VCEP, this variant was non-functional in the Kato assay and showed loss of function in additional eligible assays, supporting PS3.
TP53-specific computational assessment supports a damaging missense effect, with a VCEP worksheet assignment of PP3_moderate, BayesDel 0.598199, REVEL 0.954, and no predicted splice impact by SpliceAI (max delta score 0.00).
No criteria match.
Met · 4
PS3 StrongIn TP53 functional datasets curated by the TP53 VCEP, p.I254T was non-functional in the Kato assay and showed loss of function in the Funk, Giacomelli, and Kotler assays. This pattern is consistent with a damaging loss-of-function effect and meets TP53 PS3 at strong strength. Details ▾Hide ▴
Rule
Non-functional on Kato data and loss of function by the majority of other eligible assays.
Evidence considered
- Functional worksheet row for I254T: Kato non-functional
- Funk LOF
- Giacomelli LOF
- Kotler LOF
- preliminary functional code PS3.
- TP53 functional flowchart supports PS3 when Kato is non-functional and the majority of other eligible assays show loss of function.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0 and therefore below the TP53 PM2 threshold of less than 0.00003 (0.003%). PM2 is met at supporting strength. Details ▾Hide ▴
Rule
TP53 PM2 is applied at supporting strength for allele frequency <0.00003.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
PP3 ModerateFor this missense variant, the TP53 VCEP bioinformatic worksheet assigns PP3_moderate. The BayesDel score is 0.598199, which is above the TP53 pathogenic threshold of 0.16, REVEL is high at 0.954, and SpliceAI predicts no significant splice effect (max delta score 0.00), supporting a damaging missense interpretation rather than a splicing explanation. Details ▾Hide ▴
Rule
TP53 PP3_Moderate for missense variants uses Align-GVGD Class C65 with BayesDel ≥0.16 and no overriding splice concern.
Evidence considered
- TP53 VCEP PP3/BP4 worksheet row for c.761T>C: Align-GVGD Class C65
- BayesDel 0.598199
- preliminary code PP3_moderate.
- REVEL score 0.954.
- SpliceAI max delta score 0.00.
Sources
cspec ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelrevelspliceai ↗
Not met · 5 · evaluated, threshold not reached
PVS1 This is a missense variant, and available TP53 PVS1 materials do not place it in a null-variant category. SpliceAI predicts no splice effect (max delta score 0.00), so the TP53 PVS1 framework for truncating or splice-disrupting variants is not met. Details ▾Hide ▴
Rule
TP53 PVS1 applies to qualifying null or splice-disrupting variants; this variant does not meet that framework.
Evidence considered
- Protein consequence p.Ile254Thr is missense.
- Generic PVS1 scaffold states the variant is not in a nonsense
- frameshift
- or canonical ±1
- 2 splice bucket.
- SpliceAI max delta score is 0.00.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not reach the TP53 BA1 filtering allele frequency threshold of at least 0.001 (0.1%). Details ▾Hide ▴
Rule
TP53 BA1 requires filtering allele frequency ≥0.001.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not reach the TP53 BS1 filtering allele frequency threshold of at least 0.0003 and less than 0.001. Details ▾Hide ▴
Rule
TP53 BS1 requires filtering allele frequency ≥0.0003 and <0.001.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS3 Available functional evidence does not support retained TP53 function. Instead, TP53 VCEP-curated assays show non-functional or loss-of-function results, so BS3 is not met. Details ▾Hide ▴
Rule
TP53 BS3 requires retained or partially retained function without evidence of loss of function across eligible assays.
Evidence considered
- Functional worksheet row for I254T is preassigned PS3
- not BS3.
- Kato non-functional
- Funk LOF
- Giacomelli LOF
- Kotler LOF.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
BP4 Benign computational evidence is not supported for this missense variant. The BayesDel score is 0.598199, which is well above the TP53 benign thresholds, SpliceAI shows no splice effect (max delta score 0.00), and the TP53 VCEP bioinformatic worksheet assigns PP3_moderate rather than BP4. Details ▾Hide ▴
Rule
TP53 BP4 for missense variants requires BayesDel below pathogenic thresholds with no splice concern; this variant does not meet those conditions.
Evidence considered
- BayesDel 0.598199.
- SpliceAI max delta score 0.00.
- TP53 VCEP worksheet preassigns PP3_moderate.
Sources
cspec ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel
Not assessed · 9 · no assessment recorded
PS1 No verified evidence was identified here showing a different nucleotide change that produces the same TP53 p.Ile254Thr amino acid substitution and has already been classified as pathogenic or likely pathogenic under the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 PS1 requires the same amino acid change from a different nucleotide substitution with an eligible prior TP53 VCEP classification.
Evidence considered
- ClinVar evidence reviewed for the exact variant only.
Still missing
- Direct evidence for an alternate nucleotide change causing the same amino acid substitution was not identified.
Sources
PS2 No confirmed de novo observations with sufficient phenotype and parentage information were identified for this variant, so PS2 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
TP53 PS2 is assigned by de novo point totals.
Evidence considered
- TP53 VCEP PS2 requires point-based de novo case evidence.
Still missing
- No proven or assumed de novo cases with TP53 VCEP point scoring were identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS4 This variant meets the rarity requirement for PS4 consideration because it is absent from gnomAD, but no qualifying TP53 germline proband point total or case-control enrichment data were identified here. Therefore PS4 is not applied from the available evidence. Details ▾Hide ▴
Rule
TP53 PS4 requires PM2_Supporting first and then qualifying proband points or enrichment evidence.
Evidence considered
- Variant is absent from gnomAD v2.1 and v4.1.
- No report-ready PS4 point count was available in the reviewed materials.
Still missing
- No qualifying proband point total was identified.
- No formal case-control enrichment data were identified.
Sources
PM1 The exact amino acid change has 9 somatic observations in COSMIC, but the reviewed Cancer Hotspots result was uncertain and did not verify a TP53 VCEP-eligible hotspot assignment for this variant. Because TP53 PM1 depends on predefined hotspot codons or verified Cancer Hotspots counts, PM1 was not applied from the available evidence. Details ▾Hide ▴
Rule
TP53 PM1 requires predefined hotspot codons or verified Cancer Hotspots counts for the same amino acid change.
Evidence considered
- COSMIC reports 9 somatic occurrences for this exact variant.
- Cancer Hotspots review was flagged as uncertain.
Still missing
- A verified Cancer Hotspots residue or exact-variant count for TP53 p.Ile254Thr was not established.
Sources
PM5 No verified evidence was identified here showing that a different missense variant at TP53 codon 254 has already been classified as pathogenic or likely pathogenic under the TP53 VCEP rules at a strength that would support PM5. Details ▾Hide ▴
Rule
TP53 PM5 requires a different missense change at the same residue with an eligible prior TP53 VCEP classification.
Evidence considered
- ClinVar review confirmed the exact variant but did not establish other qualifying pathogenic missense substitutions at this residue.
Still missing
- Residue-specific prior TP53 VCEP pathogenic or likely pathogenic missense classifications at codon 254 were not established.
Sources
PP1 No segregation data were identified showing cosegregation of this variant with Li-Fraumeni syndrome-associated cancers across informative meioses, so PP1 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
TP53 PP1 is assigned by the number of informative cosegregations.
Evidence considered
- TP53 VCEP PP1 requires point-based segregation evidence across informative meioses.
Still missing
- No pedigrees with informative meiosis counts were identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 No blood variant allele fraction or equivalent constitutional mosaicism evidence was identified to assess the TP53-specific PP4 rule, so PP4 was not applied. Details ▾Hide ▴
Rule
TP53 PP4 uses variant allele fraction-based observations in blood.
Evidence considered
- TP53 VCEP PP4 is based on low-level blood VAF observations.
Still missing
- No qualifying blood VAF observation for this variant was identified.
Sources
BS2 No data were identified showing unaffected older female carriers from a single source at the counts required by the TP53 VCEP, so BS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
TP53 BS2 is assigned by counts of unrelated females at least 60 years old without cancer from a single source.
Evidence considered
- TP53 VCEP BS2 requires unaffected older female carriers from one source.
Still missing
- No qualifying unaffected carrier series was identified.
Sources
BS4 No informative family data were identified showing lack of segregation with Li-Fraumeni syndrome-associated cancers, so BS4 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
TP53 BS4 requires informative non-segregation in affected relatives.
Evidence considered
- TP53 VCEP BS4 requires lack of segregation in affected family members with relevant cancers.
Still missing
- No informative non-segregation data were identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is not used in the TP53 VCEP framework for this disorder context. Details ▾Hide ▴
PM4 N/APM4 is not used in the TP53 VCEP framework for this disorder context. Details ▾Hide ▴
PM6 N/APM6 is not used in the TP53 VCEP framework for this disorder context. Details ▾Hide ▴
PP2 N/APP2 is not used in the TP53 VCEP framework for this disorder context. 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 is a synonymous or eligible intronic variant rule and does not apply to this missense change. Details ▾Hide ▴
Evidence considered
- Variant consequence is missense: p.Ile254Thr.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.5
- Coding (HGVS c.)
- NM_000546.5:c.761T>C
- Protein (HGVS p.)
- NP_000537.3:p.(Ile254Thr)
- GRCh38
- chr17:7674202 A>G
- GRCh37
- chr17:7577520 A>G
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 ModerateFor this missense variant, the TP53 VCEP bioinformatic worksheet assigns PP3_moderate. The BayesDel score is 0.598199, which is above the TP53 pathogenic threshold of 0.16, REVEL is high at 0.954, and SpliceAI predicts no significant splice effect (max delta score 0.00), supporting a damaging missense interpretation rather than a splicing explanation. Details ▾Hide ▴
Rule
TP53 PP3_Moderate for missense variants uses Align-GVGD Class C65 with BayesDel ≥0.16 and no overriding splice concern.
Evidence considered
- TP53 VCEP PP3/BP4 worksheet row for c.761T>C: Align-GVGD Class C65
- BayesDel 0.598199
- preliminary code PP3_moderate.
- REVEL score 0.954.
- SpliceAI max delta score 0.00.
Sources
cspec ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelrevelspliceai ↗
BP4 Benign computational evidence is not supported for this missense variant. The BayesDel score is 0.598199, which is well above the TP53 benign thresholds, SpliceAI shows no splice effect (max delta score 0.00), and the TP53 VCEP bioinformatic worksheet assigns PP3_moderate rather than BP4. Details ▾Hide ▴
Rule
TP53 BP4 for missense variants requires BayesDel below pathogenic thresholds with no splice concern; this variant does not meet those conditions.
Evidence considered
- BayesDel 0.598199.
- SpliceAI max delta score 0.00.
- TP53 VCEP worksheet preassigns PP3_moderate.
Sources
cspec ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel
BP7 N/ABP7 is a synonymous or eligible intronic variant rule and does not apply to this missense change. Details ▾Hide ▴
Evidence considered
- Variant consequence is missense: p.Ile254Thr.
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.954. BayesDel score = 0.598199.
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
Open source ↗
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.761T%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7577520-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7674202-A-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.761T…
- OncoKB ↗www.oncokb.org/gene/TP53/I254T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104453324
- 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 has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.954. BayesDel score = 0.598199.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52767322, n = 9 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.