About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.925C>T, p.(Pro309Ser)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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: 1
Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1614124 alleles; AF 6.19531e-07). This frequency is below the TP53 VCEP PM2_Supporting threshold of 0.00003, and no qualifying non-founder subpopulation has multiple alleles above the 0.00004 threshold.
Benign criteria applied · 2
BS3Strong
BS3 · strong
In the TP53 VCEP functional worksheet, p.Pro309Ser is classified as functional in the Kato transactivation assay and shows no loss of function in Giacomelli functional data. This pattern supports a benign functional effect and meets BS3 under the TP53 VCEP rules.
BP4Supporting
BP4 · supporting
Computational evidence supports a benign effect. The TP53 VCEP bioinformatic worksheet assigns BP4 for c.925C>T with BayesDel 0.138442, which is below 0.16, and SpliceAI predicts no splice effect (max delta score 0.00, below the 0.2 splice-impact threshold and within the <=0.1 no-splice-impact range). REVEL is 0.607, but the TP53-specific computational framework supports BP4 for this variant.
Recorded classification: Not classified
No source classification-combination explanation was recorded.
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
1 / 1,614,124 alleles
gnomAD v4.1: 1 / 1,614,124 alleles. Recorded AF 6.19531e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
6 reported laboratory submissions
4 Uncertain significance · 1 Likely benign · 1 Uncertain Significance.
Context only
ClinVar ↗
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
COSMIC
Cancer Hotspots
Somatic evidence
5 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52729434, n = 5 times).
Cancer Hotspots
This variant does not lie 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: 3 met · 5 not met · 8 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.925C>T (p.Pro309Ser; p.P309S) variant has been observed in somatic cancers in COSMIC (COSV52729434; n=5) and has been reported in ClinVar with predominantly uncertain significance submissions and one likely benign submission.
This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1614124 alleles; AF 6.19531e-07), which is below the TP53 VCEP PM2_Supporting threshold of 0.00003.
In TP53 functional studies curated by the VCEP, Kato transactivation testing classified p.Pro309Ser as functional and Giacomelli data showed no loss of function, supporting BS3.
Computational evidence predicts no splice effect (SpliceAI max delta score 0.00), and the TP53 VCEP bioinformatic worksheet assigns BP4 for c.925C>T with BayesDel 0.138442; REVEL 0.607 was available but does not override the TP53-specific computational rule.
No criteria match.
Met · 3
PM2 SupportingThis variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1614124 alleles; AF 6.19531e-07). This frequency is below the TP53 VCEP PM2_Supporting threshold of 0.00003, and no qualifying non-founder subpopulation has multiple alleles above the 0.00004 threshold. Details ▾Hide ▴
Rule
TP53 VCEP PM2 applies at Supporting when AF < 0.00003 and no qualifying ancestry group with multiple alleles exceeds 0.00004.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AF 6.195310893091237e-07 with 1 allele observed.
Sources
BS3 StrongIn the TP53 VCEP functional worksheet, p.Pro309Ser is classified as functional in the Kato transactivation assay and shows no loss of function in Giacomelli functional data. This pattern supports a benign functional effect and meets BS3 under the TP53 VCEP rules. Details ▾Hide ▴
Rule
TP53 VCEP BS3 Strong: functional on Kato data and no loss of function by the majority of available eligible assays.
Evidence considered
- Functional worksheet row for P309S: Kato Functional
- Giacomelli noLOF
- preliminary code BS3.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:30224644 ↗
BP4 SupportingComputational evidence supports a benign effect. The TP53 VCEP bioinformatic worksheet assigns BP4 for c.925C>T with BayesDel 0.138442, which is below 0.16, and SpliceAI predicts no splice effect (max delta score 0.00, below the 0.2 splice-impact threshold and within the <=0.1 no-splice-impact range). REVEL is 0.607, but the TP53-specific computational framework supports BP4 for this variant. Details ▾Hide ▴
Rule
TP53 VCEP BP4 Supporting for missense variants applies when BayesDel is < 0.16 and > -0.008, with no predicted splicing impact (SpliceAI < 0.2).
Evidence considered
- PP3/BP4 worksheet row for c.925C>T: Class C0
- BayesDel 0.138442
- code BP4
- SpliceAI max delta 0.00.
Sources
bayesdelspliceai ↗revelvcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7cspec ↗
Not met · 5 · evaluated, threshold not reached
PS3 Available functional evidence does not support a damaging effect. TP53 functional data classify p.Pro309Ser as functional in Kato transactivation testing and as no loss of function in Giacomelli data, so PS3 is not met. Details ▾Hide ▴
Rule
TP53 VCEP PS3 requires non-functional or partially functional Kato data together with loss of function across other eligible assays.
Evidence considered
- Functional worksheet row for P309S does not assign PS3 and instead supports BS3.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:30224644 ↗
PM1 This missense variant is not in one of the TP53 hotspot codons eligible for PM1 by rule, and no Cancer Hotspots evidence was identified to confirm the same amino acid change as a qualifying somatic hotspot. COSMIC shows 5 somatic observations, but that alone does not satisfy the TP53 VCEP PM1 requirement. Details ▾Hide ▴
Rule
TP53 VCEP PM1 applies to codons 175, 245, 248, 249, 273, 282, or to qualifying Cancer Hotspots recurrence for the same amino acid change.
Evidence considered
- Cancer Hotspots review did not identify a qualifying hotspot row for P309S.
Still missing
- Independent confirmation from Cancer Hotspots would be needed if hotspot-based PM1 were considered.
Sources
PP3 Available computational evidence does not meet the TP53 VCEP PP3 threshold. BayesDel is 0.138442, which is below the PP3 cutoff of 0.16, and SpliceAI predicts no splice effect (max delta score 0.00). REVEL is 0.607, but TP53 missense PP3/BP4 assignment is governed by the TP53-specific BayesDel/aGVGD plus SpliceAI framework, and the precomputed TP53 worksheet does not assign PP3 for c.925C>T. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for missense variants requires qualifying aGVGD class with BayesDel >= 0.16, or SpliceAI >= 0.2 for splice-impact scenarios.
Evidence considered
- PP3/BP4 worksheet row for c.925C>T assigns BP4
- BayesDel 0.138442
- SpliceAI max delta 0.00
- REVEL 0.607.
Sources
bayesdelspliceai ↗revelvcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7cspec ↗
BA1 The population frequency is far below the TP53 VCEP BA1 threshold. In gnomAD v4.1, this variant is present at 1/1614124 alleles (AF 6.19531e-07), which is below the BA1 cutoff of 0.001. Details ▾Hide ▴
Rule
TP53 VCEP BA1 requires FAF >= 0.001 in a qualifying subpopulation.
Evidence considered
- gnomAD v4.1 total AF 6.195310893091237e-07 (1/1614124 alleles).
Sources
BS1 The population frequency does not meet the TP53 VCEP BS1 threshold. In gnomAD v4.1, this variant is present at 1/1614124 alleles (AF 6.19531e-07), which is below the BS1 cutoff of 0.0003, and no qualifying subpopulation frequency was identified. Details ▾Hide ▴
Rule
TP53 VCEP BS1 requires FAF >= 0.0003 and < 0.001 in a qualifying subpopulation.
Evidence considered
- gnomAD v4.1 total AF 6.195310893091237e-07 (1/1614124 alleles).
Sources
Not assessed · 8 · no assessment recorded
PS1 No previously established TP53 VCEP pathogenic or likely pathogenic variant producing the same amino acid change was identified from the available evidence. Details ▾Hide ▴
PS2 No confirmed de novo observations with the cancer-point information required by the TP53 VCEP were identified. Details ▾Hide ▴
Evidence considered
- TP53 VCEP PS2 requires point-based de novo evidence.
Still missing
- Parental testing and proband cancer details were not available.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS4 PM2_Supporting is met, but no proband-level Li-Fraumeni syndrome cancer point data were identified to score PS4 under the TP53 VCEP point system. Details ▾Hide ▴
Evidence considered
- TP53 VCEP PS4 requires case-point evidence after population review.
Still missing
- Published or laboratory case observations with TP53 VCEP PS4 point assignments were not available.
Sources
cspec ↗vcep_ps4_points_table
PM5 TP53 uses classic same-residue missense PM5 logic, but no previously established TP53 VCEP pathogenic or qualifying likely pathogenic comparator at codon 309 was identified from the available evidence. Details ▾Hide ▴
Evidence considered
- No qualifying same-residue comparator was established from the available PM5 candidate review.
Still missing
- A validated TP53 VCEP same-residue comparator would be needed before PM5 could be applied.
Sources
cspec ↗pm5_candidates
PP1 No segregation data were identified to assess cosegregation with Li-Fraumeni syndrome-associated cancers. Details ▾Hide ▴
Evidence considered
- TP53 VCEP PP1 requires 3 or more informative meioses.
Still missing
- Family meiosis counts and phenotype data were not available.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 No constitutional mosaicism data or blood variant allele fraction observations in the 5-35% range were identified, so TP53-specific PP4 could not be assessed. Details ▾Hide ▴
Evidence considered
- TP53 VCEP PP4 requires low-VAF constitutional observations.
Still missing
- Case-level VAF data and tissue context were not available.
Sources
BS2 No single-source dataset of unrelated females aged 60 years or older without cancer carrying this variant was identified, so BS2 could not be assessed. Details ▾Hide ▴
Evidence considered
- TP53 VCEP BS2 requires unaffected older female carriers from one source.
Still missing
- Eligible unaffected carrier observations from a single source were not available.
Sources
BS4 No family segregation data were identified to assess lack of segregation with Li-Fraumeni syndrome-associated cancers. Details ▾Hide ▴
Evidence considered
- TP53 VCEP BS4 requires lack of segregation in affected relatives.
Still missing
- Pedigree-level segregation data were not available.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution and does not fall into the TP53 PVS1 null-variant or canonical splice-variant framework. The generic PVS1 scaffold also indicates that it is not a nonsense, frameshift, or canonical ±1,2 splice variant. Details ▾Hide ▴
Evidence considered
- TP53 PVS1 framework is available but the variant is outside PVS1-eligible classes.
Sources
PM3 VCEPThis criterion is not applicable in the TP53 VCEP specification. Details ▾Hide ▴
PM4 VCEPThis criterion is not applicable in the TP53 VCEP specification. Details ▾Hide ▴
PM6 VCEPThis criterion is not applicable in the TP53 VCEP specification. Details ▾Hide ▴
PP2 VCEPThis criterion is not applicable in the TP53 VCEP specification. Details ▾Hide ▴
PP5 VCEPThis criterion is not used in the TP53 VCEP specification. Details ▾Hide ▴
BP1 VCEPThis criterion is not applicable in the TP53 VCEP specification. Details ▾Hide ▴
BP2 VCEPThis criterion is not applicable in the TP53 VCEP specification. Details ▾Hide ▴
BP3 VCEPThis criterion is not applicable in the TP53 VCEP specification. Details ▾Hide ▴
BP5 VCEPThis criterion is not applicable in the TP53 VCEP specification. Details ▾Hide ▴
BP6 VCEPThis criterion is not used in the TP53 VCEP specification. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or relevant intronic variants, and this is a missense variant. Details ▾Hide ▴
Evidence considered
- Variant consequence is p.(Pro309Ser).
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.6
- Coding (HGVS c.)
- NM_000546.6:c.925C>T
- Protein (HGVS p.)
- NP_000537.3:p.(Pro309Ser)
- GRCh38
- chr17:7673603 G>A
- GRCh37
- chr17:7576921 G>A
- ClinVar
- 458575
- COSMIC
- COSV52729434
Gene diagram
Every interpreted variant in TP53, mapped onto the exon structure of NM_000546.6. Select a row to find it on the plot.
TP53NM_000546.6
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
1 / 1,614,124 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,124 alleles · 0 hom
| Remaining individuals1 / 62,512 | 1.6e-05 |
0 alternate alleles recorded in 9 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19531e-07; MAF= 0.00006%, 1/1614124 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59969e-05; MAF= 0.00160%, 1/62512 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.607
- BayesDel
- 0.138
How the predictions were used
BP4 SupportingComputational evidence supports a benign effect. The TP53 VCEP bioinformatic worksheet assigns BP4 for c.925C>T with BayesDel 0.138442, which is below 0.16, and SpliceAI predicts no splice effect (max delta score 0.00, below the 0.2 splice-impact threshold and within the <=0.1 no-splice-impact range). REVEL is 0.607, but the TP53-specific computational framework supports BP4 for this variant. Details ▾Hide ▴
Rule
TP53 VCEP BP4 Supporting for missense variants applies when BayesDel is < 0.16 and > -0.008, with no predicted splicing impact (SpliceAI < 0.2).
Evidence considered
- PP3/BP4 worksheet row for c.925C>T: Class C0
- BayesDel 0.138442
- code BP4
- SpliceAI max delta 0.00.
Sources
bayesdelspliceai ↗revelvcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7cspec ↗
PP3 Available computational evidence does not meet the TP53 VCEP PP3 threshold. BayesDel is 0.138442, which is below the PP3 cutoff of 0.16, and SpliceAI predicts no splice effect (max delta score 0.00). REVEL is 0.607, but TP53 missense PP3/BP4 assignment is governed by the TP53-specific BayesDel/aGVGD plus SpliceAI framework, and the precomputed TP53 worksheet does not assign PP3 for c.925C>T. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for missense variants requires qualifying aGVGD class with BayesDel >= 0.16, or SpliceAI >= 0.2 for splice-impact scenarios.
Evidence considered
- PP3/BP4 worksheet row for c.925C>T assigns BP4
- BayesDel 0.138442
- SpliceAI max delta 0.00
- REVEL 0.607.
Sources
bayesdelspliceai ↗revelvcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7cspec ↗
BP7 N/ABP7 applies to synonymous or relevant intronic variants, and this is a missense variant. Details ▾Hide ▴
Evidence considered
- Variant consequence is p.(Pro309Ser).
Sources
cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 12826609 ↗Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.Kato S et al. · 2003No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
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PMID 29300620 ↗TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children.Qian M et al. · 2018No paper-specific finding is recorded.
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PMID 29979965 ↗A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.Kotler E et al. · 2018No paper-specific finding is recorded.
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PMID 30224644 ↗Mutational processes shape the landscape of TP53 mutations in human cancer.Giacomelli AO et al. · 2018No paper-specific finding is recorded.
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PMID 34793697 ↗Closing the gap: Systematic integration of multiplexed functional data resolves variants of uncertain significance in BRCA1, TP53, and PTEN.No paper-specific finding is recorded.
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PMID 38645101 ↗Defining and Reducing Variant Classification Disparities.No paper-specific finding is recorded.
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PMID 12692171 ↗American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,614,124 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
4 Uncertain significance · 1 Likely benign · 1 Uncertain Significance
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/variation/458575/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7576921-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7673603-G-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.925C…
- OncoKB ↗www.oncokb.org/gene/TP53/P309S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104410116
- 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
This variant is present in gnomAD v4.1 (AF= 6.19531e-07; MAF= 0.00006%, 1/1614124 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59969e-05; MAF= 0.00160%, 1/62512 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 458575)
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV52729434, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.