About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.469G>T, p.(Val157Phe)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PS3Strong
PS3 · strong
In the TP53 VCEP functional worksheet, p.(Val157Phe) is assigned PS3. The worksheet records non-functional Kato transactivation results and loss-of-function findings across the majority of other eligible assays, which supports a damaging effect on normal p53 function.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0/1,614,132 alleles observed in gnomAD v4.1 (AF 0.0). This is below the TP53 VCEP PM2 threshold of less than 0.00003, so PM2_Supporting is met.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) = 5 points, which maps to VUS.
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
0 / 1,614,132 alleles
gnomAD v4.1: 0 / 1,614,132 alleles. Recorded AF 0. 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.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
6 reported laboratory submissions
4 Likely pathogenic · 2 Pathogenic.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
375 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52667015, n = 375 times).
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: 2 met · 5 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 NM_000546.6:c.469G>T (p.Val157Phe, p.V157F) variant has been reported in ClinVar with Likely pathogenic and Pathogenic clinical submissions.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, including 0 of 1,614,132 alleles in gnomAD v4.1, which supports PM2_Supporting under the TP53 VCEP threshold of less than 0.00003.
In the TP53 VCEP functional framework, p.Val157Phe is assigned PS3 because Kato-based transactivation results are non-functional and the majority of other eligible assays show loss of function; additional published studies describe abnormal mutant behavior and structural destabilization consistent with impaired normal p53 activity.
SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and although REVEL is 0.708 and BayesDel is 0.314073, the TP53 VCEP precomputed in silico table assigns c.469G>T as 'No evidence', so neither PP3 nor BP4 was applied.
No criteria match.
Met · 2
PS3 StrongIn the TP53 VCEP functional worksheet, p.(Val157Phe) is assigned PS3. The worksheet records non-functional Kato transactivation results and loss-of-function findings across the majority of other eligible assays, which supports a damaging effect on normal p53 function. Details ▾Hide ▴
Rule
TP53 PS3 Strong: non-functional on Kato data and LOF by the majority of other eligible assays.
Evidence considered
- TP53 VCEP functional worksheet row: V157F -> PS3
- worksheet values include Non-functional and majority LOF calls
- published exact-variant studies describe abnormal mutant behavior and structural destabilization
Sources
cspec ↗vcep_flowchart_for_application_of_functional_rule_codesvcep_functional_worksheetPMID:16778209 ↗PMID:21561095 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0/1,614,132 alleles observed in gnomAD v4.1 (AF 0.0). This is below the TP53 VCEP PM2 threshold of less than 0.00003, so PM2_Supporting is met. Details ▾Hide ▴
Rule
TP53 PM2 is applied at Supporting strength for AF < 0.00003.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AC 0 / AN 1614132
- AF 0.0
Sources
Not met · 5 · evaluated, threshold not reached
PP3 Computational results show REVEL 0.708, BayesDel 0.314073, and no predicted splice effect by SpliceAI (max delta score 0.00). However, the TP53 VCEP precomputed PP3/BP4 table lists NM_000546.6:c.469G>T as 'No evidence', so PP3 was not applied. Details ▾Hide ▴
Rule
TP53 PP3 uses the VCEP missense flowchart and precomputed code assignments.
Evidence considered
- REVEL 0.708
- BayesDel 0.314073
- SpliceAI max delta score 0.00
- TP53 VCEP PP3-BP4 table assignment: No evidence
Sources
cspec ↗revelbayesdelspliceai ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BA1 This variant is absent from gnomAD v4.1 (0/1,614,132 alleles; AF 0.0), which is below the TP53 VCEP BA1 threshold of at least 0.001. BA1 is not met. Details ▾Hide ▴
Rule
TP53 BA1 requires FAF at least 0.001 in a qualifying population.
Evidence considered
- gnomAD v4.1 AF 0.0
Sources
BS1 This variant is absent from gnomAD v4.1 (0/1,614,132 alleles; AF 0.0), which is below the TP53 VCEP BS1 threshold of at least 0.0003. BS1 is not met. Details ▾Hide ▴
Rule
TP53 BS1 requires FAF at least 0.0003 in a qualifying population.
Evidence considered
- gnomAD v4.1 AF 0.0
Sources
BS3 Available functional evidence does not show retained or near-normal p53 activity. Instead, the TP53 VCEP functional worksheet assigns p.(Val157Phe) to PS3, so BS3 is not met. Details ▾Hide ▴
Rule
TP53 BS3 requires no loss of function in the eligible assay framework.
Evidence considered
- TP53 VCEP functional worksheet assignment: PS3
- no wild-type-like functional dataset identified
Sources
cspec ↗vcep_flowchart_for_application_of_functional_rule_codesvcep_functional_worksheetPMID:16778209 ↗PMID:21561095 ↗
BP4 SpliceAI predicts no splice effect (max delta score 0.00), but BayesDel is 0.314073 rather than below the benign thresholds, and the TP53 VCEP precomputed PP3/BP4 table assigns NM_000546.6:c.469G>T as 'No evidence'. BP4 is not met. Details ▾Hide ▴
Rule
TP53 BP4 uses the VCEP missense flowchart and precomputed code assignments.
Evidence considered
- BayesDel 0.314073
- SpliceAI max delta score 0.00
- TP53 VCEP PP3-BP4 table assignment: No evidence
Sources
Not assessed · 9 · no assessment recorded
PS1 No previously classified TP53 variant producing the same amino acid change through a different nucleotide substitution was confirmed, so PS1 was not applied. Details ▾Hide ▴
PS2 No confirmed de novo occurrence of this exact variant with interpretable TP53 VCEP point scoring was identified, so PS2 was not applied. Details ▾Hide ▴
Rule
TP53 PS2 requires de novo evidence meeting the point-based thresholds.
Evidence considered
- no exact-variant de novo evidence confirmed in reviewed materials
Still missing
- No maternity/paternity-confirmed de novo case for this exact variant was identified.
- No TP53 VCEP point total could be assigned from the available reports.
Sources
PS4 This variant has been reported in ClinVar, but no proband-level Li-Fraumeni syndrome point total meeting TP53 VCEP PS4 thresholds was established from the available evidence. PS4 was therefore not applied. Details ▾Hide ▴
Rule
TP53 PS4 requires case observations reaching the point-based thresholds after PM2_Supporting is met.
Evidence considered
- ClinVar has multiple pathogenic/likely pathogenic submissions
- no confirmed TP53 VCEP PS4 point total
Still missing
- No independent affected-proband count with TP53 VCEP PS4 point scoring was confirmed.
- No exact PS4 points table total could be derived from the available reports.
Sources
PM1 Codon 157 is not one of the TP53 codons that automatically qualify for PM1, and the available Cancer Hotspots review did not verify an exact hotspot count for this amino acid change. PM1 was not applied from the current evidence. Details ▾Hide ▴
Rule
TP53 PM1 requires one of the specified codons or a verified Cancer Hotspots count for the exact amino acid change.
Evidence considered
- TP53 automatic PM1 codons do not include 157
- Cancer Hotspots assessment remained uncertain
Still missing
- Exact Cancer Hotspots count for p.(Val157Phe) was not verified.
Sources
PM5 No validated same-residue TP53 comparator variant meeting the TP53 VCEP PM5 requirements was confirmed, so PM5 was not applied. Details ▾Hide ▴
Rule
TP53 PM5 requires a previously classified same-residue missense comparator under TP53 VCEP rules.
Evidence considered
- no validated same-residue comparator confirmed from reviewed materials
Still missing
- No confirmed TP53 VCEP pathogenic or likely pathogenic same-residue comparator was established.
Sources
PP1 No segregation data with enough informative meioses to meet TP53 VCEP thresholds were identified, so PP1 was not applied. Details ▾Hide ▴
Rule
TP53 PP1 requires 3-4, 5-6, or at least 7 informative meioses depending on strength.
Evidence considered
- no qualifying segregation evidence identified
Still missing
- No family segregation dataset with 3 or more informative meioses was identified.
Sources
PP4 No low-variant-allele-fraction constitutional mosaic observation meeting the TP53 VCEP PP4 requirements was identified, so PP4 was not applied. Details ▾Hide ▴
Rule
TP53 PP4 is a mosaicism-based criterion with VAF thresholds.
Evidence considered
- no qualifying low-VAF constitutional mosaic observation confirmed
Still missing
- No exact qualifying observation with VAF 5-35% was identified.
Sources
BS2 No source documenting unaffected older female carriers in numbers sufficient for TP53 VCEP BS2 was identified, so BS2 was not applied. Details ▾Hide ▴
Rule
TP53 BS2 requires unaffected older female carriers from a single source.
Evidence considered
- no qualifying unaffected-carrier dataset identified
Still missing
- No single source with 2 or more unrelated cancer-free female carriers aged at least 60 years was identified.
Sources
BS4 No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified, so BS4 was not applied. Details ▾Hide ▴
Rule
TP53 BS4 requires lack of segregation in affected relatives with relevant cancers.
Evidence considered
- no qualifying nonsegregation evidence identified
Still missing
- No nonsegregation pedigree for this exact variant was identified.
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, p.(Val157Phe), and does not fall into the TP53 null-variant or canonical splice categories used for PVS1. SpliceAI predicts no meaningful splice effect (max delta score 0.00), so available evidence does not support applying PVS1. Details ▾Hide ▴
Rule
TP53 PVS1 applies to null/splice categories, not this missense variant.
Evidence considered
- NM_000546.6:c.469G>T encodes p.(Val157Phe)
- generic PVS1 scaffold: not in nonsense/frameshift/canonical splice buckets
- SpliceAI max delta score 0.00
Sources
PM3 VCEPPM3 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
PM4 VCEPPM4 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
PM6 VCEPPM6 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
PP2 VCEPPP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
PP5 VCEPPP5 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP2 VCEPBP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP3 VCEPBP3 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP5 VCEPBP5 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP6 VCEPBP6 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or certain intronic variants without predicted splice impact. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
TP53 BP7 is limited to synonymous or intronic variants.
Evidence considered
- variant is missense
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.469G>T
- Protein (HGVS p.)
- NP_000537.3:p.(Val157Phe)
- GRCh38
- chr17:7675143 C>A
- GRCh37
- chr17:7578461 C>A
- ClinVar
- 12353, 915695, 428887
- COSMIC
- COSV52667015
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
0 / 1,614,132 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,614,132 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1614132 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75036 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.708
- BayesDel
- 0.314
How the predictions were used
PP3 Computational results show REVEL 0.708, BayesDel 0.314073, and no predicted splice effect by SpliceAI (max delta score 0.00). However, the TP53 VCEP precomputed PP3/BP4 table lists NM_000546.6:c.469G>T as 'No evidence', so PP3 was not applied. Details ▾Hide ▴
Rule
TP53 PP3 uses the VCEP missense flowchart and precomputed code assignments.
Evidence considered
- REVEL 0.708
- BayesDel 0.314073
- SpliceAI max delta score 0.00
- TP53 VCEP PP3-BP4 table assignment: No evidence
Sources
cspec ↗revelbayesdelspliceai ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP4 SpliceAI predicts no splice effect (max delta score 0.00), but BayesDel is 0.314073 rather than below the benign thresholds, and the TP53 VCEP precomputed PP3/BP4 table assigns NM_000546.6:c.469G>T as 'No evidence'. BP4 is not met. Details ▾Hide ▴
Rule
TP53 BP4 uses the VCEP missense flowchart and precomputed code assignments.
Evidence considered
- BayesDel 0.314073
- SpliceAI max delta score 0.00
- TP53 VCEP PP3-BP4 table assignment: No evidence
Sources
BP7 N/ABP7 applies to synonymous or certain intronic variants without predicted splice impact. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
TP53 BP7 is limited to synonymous or intronic variants.
Evidence considered
- variant is missense
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 = 0.708. BayesDel score = 0.314073.
7 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 15037740 ↗A global suppressor motif for p53 cancer mutants.Baroni TE et al. · 2004No paper-specific finding is recorded.
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PMID 16778209 ↗Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1 for RhoA, resulting in accelerated cell proliferation in tumor cells.No paper-specific finding is recorded.
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PMID 21561095 ↗Structural effects of the L145Q, V157F, and R282W cancer-associated mutations in the p53 DNA-binding core domain.No paper-specific finding is recorded.
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PMID 10713666 ↗Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy.Bullock AN et al. · 2000No paper-specific finding is recorded.
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PMID 10754498 ↗Clinical significance of p53 functional loss in squamous cell carcinoma of the oropharynx.Obata A et al. · 2000No paper-specific finding is recorded.
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PMID 27993330 ↗Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists.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
0 / 1,614,132 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 Likely pathogenic · 2 Pathogenic
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/12353/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7578461-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7675143-C-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.469G…
- OncoKB ↗www.oncokb.org/gene/TP53/V157F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121487438
- 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= 0; MAF= 0.00000%, 0/1614132 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75036 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Pathogenic (2 clinical laboratories). (ClinVarID = 12353)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.708. BayesDel score = 0.314073.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52667015, n = 375 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.