About TP53
No gene-level summary was recorded for this case.
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Variant interpretation report
TP53 c.245C>T, p.(Pro82Leu)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign 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: 1
Benign evidence criteria: 3
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is rare in population databases. The overall allele frequency is 1.99644e-05 in gnomAD v2.1 and 1.11599e-05 in gnomAD v4.1, both below the TP53 VCEP PM2 threshold of 0.00003, and no non-founder ancestry group with multiple alleles exceeds the 0.00004 cutoff, so PM2 is met at supporting strength.
Benign criteria applied · 3
BS3Strong
BS3 · strong
In the TP53 VCEP functional worksheet, p.Pro82Leu (P82L) is assigned BS3, and the summarized assay interpretation is functional with no loss-of-function, supporting retained TP53 protein function.
BP4Supporting
BP4 · supporting
Available computational evidence supports a benign interpretation under the TP53 VCEP missense framework. The TP53 PP3/BP4 worksheet lists c.245C>T (p.Pro82Leu) as Class C0 with BayesDel 0.0708215 and assigns BP4, and SpliceAI predicts no splice effect with a max delta score of 0.00. REVEL is 0.57, but the TP53 VCEP precomputed code for this missense change is BP4.
BP6Supporting
BP6 · supporting
Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely benign.
Recorded classification: Likely benign
TP53 VCEP v2.4.0 CSPEC Tavtigian point-based final-classification framework; BS3_Strong (-4), BP4 (-1), BP6 (-1), and PM2_Supporting (+1) yield a net score of -5 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
18 / 1,612,916 alleles
gnomAD v4.1: 18 / 1,612,916 alleles. Recorded AF 1.11599e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.99644e-05; MAF= 0.00200%, 5/250446 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.36375e-05; MAF= 0.00636%, 1/15714 alleles, homozygotes = 0); grpmax FAF= 7.03e-06.
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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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: 4 met · 5 not met · 8 not assessed · 11 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.245C>T (p.Pro82Leu) variant has been reported in ClinVar, where the aggregate classification is Likely Benign with expert panel review.
This variant is present at very low frequency in gnomAD v2.1 and v4.1 (overall AF 1.99644e-05 and 1.11599e-05; grpmax FAF 7.03e-06 and 8.76e-06), which is below the TP53 VCEP PM2_Supporting threshold of 0.00003 overall and below 0.00004 in any non-founder ancestry group with multiple alleles.
In the TP53 VCEP functional worksheet, p.Pro82Leu (P82L) is assigned BS3 and the summarized assay interpretation is functional with no loss-of-function, supporting retained protein function.
Computational assessment under the TP53 VCEP missense framework lists c.245C>T as Class C0 with BayesDel 0.0708215 and BP4, while SpliceAI predicts no splice impact (max delta 0.00); REVEL is 0.57 but does not override the TP53 VCEP benign computational assignment for this variant.
No criteria match.
Met · 4
PM2 SupportingThis variant is rare in population databases. The overall allele frequency is 1.99644e-05 in gnomAD v2.1 and 1.11599e-05 in gnomAD v4.1, both below the TP53 VCEP PM2 threshold of 0.00003, and no non-founder ancestry group with multiple alleles exceeds the 0.00004 cutoff, so PM2 is met at supporting strength. Details ▾Hide ▴
Rule
PM2_Supporting
Evidence considered
- gnomAD v2.1 AF 1.99644e-05.
- gnomAD v4.1 AF 1.11599e-05.
- AMR in gnomAD v4.1 has 2 alleles with AF 3.33467e-05
- below 0.00004.
- TP53 VCEP applies PM2 at supporting strength only.
Sources
BS3 StrongIn the TP53 VCEP functional worksheet, p.Pro82Leu (P82L) is assigned BS3, and the summarized assay interpretation is functional with no loss-of-function, supporting retained TP53 protein function. Details ▾Hide ▴
Rule
BS3
Evidence considered
- Functional worksheet row: P82L | Functional | noLOF | BS3.
- TP53 VCEP functional flowchart supports BS3 for retained function.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codes
BP4 SupportingAvailable computational evidence supports a benign interpretation under the TP53 VCEP missense framework. The TP53 PP3/BP4 worksheet lists c.245C>T (p.Pro82Leu) as Class C0 with BayesDel 0.0708215 and assigns BP4, and SpliceAI predicts no splice effect with a max delta score of 0.00. REVEL is 0.57, but the TP53 VCEP precomputed code for this missense change is BP4. Details ▾Hide ▴
Rule
BP4
Evidence considered
- TP53 worksheet entry: c.245C>T | p.Pro82Leu | Class C0 | 0.0708215 | BP4.
- SpliceAI max delta score 0.00.
- REVEL score 0.57.
Sources
Not met · 5 · evaluated, threshold not reached
PS3 Available functional evidence does not support a damaging effect. The TP53 VCEP functional worksheet assigns BS3 rather than PS3 for p.Pro82Leu, with summarized results indicating functional activity and no loss-of-function. Details ▾Hide ▴
Evidence considered
- Functional worksheet row for P82L is assigned BS3 with functional/noLOF summary.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codes
PM1 This missense variant affects codon 82, which is outside the TP53 VCEP codons that qualify directly for PM1 (175, 245, 248, 249, 273, 282), and no verified hotspot evidence showing at least 2 somatic occurrences for this exact amino acid change was identified in the reviewed evidence. Details ▾Hide ▴
Evidence considered
- Codon 82 is not among the TP53 VCEP PM1 hotspot codons.
- Cancer Hotspots review did not show a statistically significant hotspot row for this variant.
Still missing
- Independent residue-level hotspot confirmation for p.Pro82Leu was not identified.
Sources
PP3 Available computational evidence does not support a damaging effect under the TP53 VCEP in silico framework. The TP53 PP3/BP4 worksheet lists c.245C>T as Class C0 with BayesDel 0.0708215 and BP4, and SpliceAI predicts no splice impact with a max delta score of 0.00. REVEL is available at 0.57, but the TP53 VCEP missense rule for this variant supports BP4 rather than PP3. Details ▾Hide ▴
Evidence considered
- TP53 worksheet entry: c.245C>T | p.Pro82Leu | Class C0 | 0.0708215 | BP4.
- SpliceAI max delta score 0.00.
- REVEL score 0.57.
Sources
BA1 The highest observed filtering allele frequency is 7.03e-06 in gnomAD v2.1 and 8.76e-06 in gnomAD v4.1, which is below the TP53 VCEP BA1 threshold of 0.001, so BA1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF 7.03e-06.
- gnomAD v4.1 grpmax FAF 8.76e-06.
- TP53 VCEP BA1 threshold is >=0.001.
Sources
BS1 The highest observed filtering allele frequency is 7.03e-06 in gnomAD v2.1 and 8.76e-06 in gnomAD v4.1, which is below the TP53 VCEP BS1 threshold of 0.0003, so BS1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF 7.03e-06.
- gnomAD v4.1 grpmax FAF 8.76e-06.
- TP53 VCEP BS1 threshold is >=0.0003.
Sources
Not assessed · 8 · no assessment recorded
PS1 No previously established TP53 VCEP pathogenic or likely pathogenic variant with the same amino acid change was identified in the reviewed evidence, so PS1 cannot be assigned from the available data. Details ▾Hide ▴
PS2 No confirmed de novo observation with the TP53 VCEP point-based evidence required for PS2 was identified. Details ▾Hide ▴
Evidence considered
- TP53 VCEP PS2 requires point-based de novo evidence.
Still missing
- No documented de novo case with confirmed parentage was identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS4 No countable affected probands or Li-Fraumeni syndrome point total were identified for this variant, so PS4 cannot be applied even though the population frequency is low enough for PM2_Supporting. Details ▾Hide ▴
Evidence considered
- TP53 VCEP PS4 requires affected-individual point scoring.
- Population frequency remains low.
Still missing
- No proband-level clinical observations with TP53 VCEP PS4 point scoring were identified.
Sources
PM5 No reviewed evidence identified previously established TP53 VCEP pathogenic or likely pathogenic missense variants at codon 82 that would support PM5. Details ▾Hide ▴
PP1 No segregation data with countable meioses were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
Evidence considered
- TP53 VCEP PP1 requires 3 or more informative meioses.
Still missing
- No family segregation data were identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 No blood variant allele fraction or comparable mosaicism data were identified, so the TP53 VCEP PP4 thresholds based on low variant allele fraction observations cannot be evaluated. Details ▾Hide ▴
Evidence considered
- TP53 VCEP PP4 depends on one or more observations with VAF 5-35%.
Still missing
- Variant allele fraction data from clinical observations were not available.
Sources
BS2 No dataset of unrelated females aged 60 years or older without cancer who carry this variant was identified, so BS2 cannot be evaluated. Details ▾Hide ▴
Evidence considered
- TP53 VCEP BS2 requires unaffected older female carriers from a single source.
Still missing
- No unaffected-carrier dataset meeting TP53 VCEP BS2 requirements was identified.
Sources
BS4 No segregation study showing lack of segregation with Li-Fraumeni syndrome-associated cancers was identified, so BS4 cannot be evaluated. Details ▾Hide ▴
Evidence considered
- TP53 VCEP BS4 requires lack of segregation in affected family members.
Still missing
- No family segregation or non-segregation data were identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution with no predicted splice effect and does not fall into the TP53 or generic PVS1 null-variant categories such as nonsense, frameshift, or canonical splice-site change, so PVS1 is not applicable. Details ▾Hide ▴
Evidence considered
- TP53 is eligible for PVS1 in the appropriate null-variant context.
- This variant is not a null variant.
- SpliceAI max delta score is 0.00.
Sources
PM3 N/AThe TP53 VCEP does not use PM3 for variant classification. Details ▾Hide ▴
PM4 N/AThe TP53 VCEP does not use PM4 for variant classification, and this variant is not an in-frame insertion or deletion. Details ▾Hide ▴
PM6 N/AThe TP53 VCEP does not use PM6 for variant classification. Details ▾Hide ▴
PP2 N/AThe TP53 VCEP does not use PP2 for variant classification. Details ▾Hide ▴
PP5 N/AThe TP53 VCEP does not use PP5 for variant classification. Details ▾Hide ▴
BP1 N/AThe TP53 VCEP does not use BP1 for variant classification. Details ▾Hide ▴
BP2 N/AThe TP53 VCEP does not use BP2 for variant classification. Details ▾Hide ▴
BP3 N/AThe TP53 VCEP does not use BP3 for variant classification. Details ▾Hide ▴
BP5 N/AThe TP53 VCEP does not use BP5 for variant classification. Details ▾Hide ▴
BP7 N/AThis is a missense variant, not a synonymous or intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant consequence is p.(Pro82Leu).
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.245C>T
- Protein (HGVS p.)
- NP_000537.3:p.(Pro82Leu)
- GRCh38
- chr17:7676124 G>A
- GRCh37
- chr17:7579442 G>A
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
18 / 1,612,916 alleles
AF 1.12e-05 · 0 homozygotes · FAF 8.76e-06
gnomAD v2.1
5 / 250,446 alleles
AF 2e-05 · 0 homozygotes · FAF 7.03e-06
By genetic ancestry
gnomAD v4.1
AF 1.1e-05 · 18 / 1,612,916 alleles · 0 hom · FAF 8.8e-06
| Ashkenazi Jewish1 / 29,600 | 3.4e-05 |
| Admixed American2 / 59,976 | 3.3e-05 |
| South Asian3 / 91,024 | 3.3e-05 |
| African/African American2 / 74,994 | 2.7e-05 |
| Remaining individuals1 / 62,420 | 1.6e-05 |
| European (non-Finnish)9 / 1,179,646 | 7.6e-06 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, Middle Eastern.
gnomAD v2.1
AF 2e-05 · 5 / 250,446 alleles · 0 hom · FAF 7e-06
| African/African American1 / 15,714 | 6.4e-05 |
| South Asian1 / 30,614 | 3.3e-05 |
| European (non-Finnish)3 / 113,356 | 2.6e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.11599e-05; MAF= 0.00112%, 18/1612916 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37838e-05; MAF= 0.00338%, 1/29600 alleles, homozygotes = 0); grpmax FAF= 8.76e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.99644e-05; MAF= 0.00200%, 5/250446 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.36375e-05; MAF= 0.00636%, 1/15714 alleles, homozygotes = 0); grpmax FAF= 7.03e-06.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingAvailable computational evidence supports a benign interpretation under the TP53 VCEP missense framework. The TP53 PP3/BP4 worksheet lists c.245C>T (p.Pro82Leu) as Class C0 with BayesDel 0.0708215 and assigns BP4, and SpliceAI predicts no splice effect with a max delta score of 0.00. REVEL is 0.57, but the TP53 VCEP precomputed code for this missense change is BP4. Details ▾Hide ▴
Rule
BP4
Evidence considered
- TP53 worksheet entry: c.245C>T | p.Pro82Leu | Class C0 | 0.0708215 | BP4.
- SpliceAI max delta score 0.00.
- REVEL score 0.57.
Sources
PP3 Available computational evidence does not support a damaging effect under the TP53 VCEP in silico framework. The TP53 PP3/BP4 worksheet lists c.245C>T as Class C0 with BayesDel 0.0708215 and BP4, and SpliceAI predicts no splice impact with a max delta score of 0.00. REVEL is available at 0.57, but the TP53 VCEP missense rule for this variant supports BP4 rather than PP3. Details ▾Hide ▴
Evidence considered
- TP53 worksheet entry: c.245C>T | p.Pro82Leu | Class C0 | 0.0708215 | BP4.
- SpliceAI max delta score 0.00.
- REVEL score 0.57.
Sources
BP7 N/AThis is a missense variant, not a synonymous or intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant consequence is p.(Pro82Leu).
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 = 0.57. BayesDel score = 0.0708215.
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
18 / 1,612,916 recorded alleles
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/variation/182946/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7579442-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7676124-G-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.5%3Ac.245C…
- OncoKB ↗www.oncokb.org/gene/TP53/P82L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104453309
- 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= 1.11599e-05; MAF= 0.00112%, 18/1612916 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37838e-05; MAF= 0.00338%, 1/29600 alleles, homozygotes = 0); grpmax FAF= 8.76e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.99644e-05; MAF= 0.00200%, 5/250446 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.36375e-05; MAF= 0.00636%, 1/15714 alleles, homozygotes = 0); grpmax FAF= 7.03e-06.
ClinVar
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Benign (1 clinical laboratory) and as Likely Benign (1 clinical laboratory) and as Likely Benign 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 = 0.57. BayesDel score = 0.0708215.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53209087, n = 11 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.