About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.373A>C, p.(Thr125Pro)
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 evidence supports a damaging effect. In the TP53 VCEP functional worksheet, p.(Thr125Pro) is listed as non-functional in Kato data and loss-of-function in additional eligible assays, with a pre-assigned PS3 code. This is consistent with a deleterious effect on TP53 protein function.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1. Its observed population frequency is therefore below the TP53 VCEP PM2_Supporting threshold of less than 0.00003 overall and below the per-ancestry multiple-allele threshold of less than 0.00004.
PP3Supporting
PP3 · supporting
TP53 in silico evidence supports a deleterious effect. In the TP53 VCEP PP3/BP4 worksheet, c.373A>C is assigned PP3 with aGVGD Class C35 and BayesDel score 0.576078. SpliceAI predicts no significant splice impact with a max delta score of 0.09, so the evidence supports a missense damaging effect rather than a splice-driven benign interpretation.
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 supporting (+1) = 6 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.
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
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.373A>C (p.Thr125Pro) variant has been observed in somatic cancer knowledgebases and has been reported in ClinVar with conflicting germline classifications, including Likely pathogenic and uncertain significance submissions.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity and meeting the TP53 VCEP PM2_Supporting population threshold of less than 0.00003.
TP53 functional data support a damaging effect, with the TP53 VCEP functional worksheet listing p.(Thr125Pro) as non-functional with loss of function across eligible assays and assigning PS3.
TP53 in silico evidence also supports deleteriousness: the TP53 VCEP PP3/BP4 worksheet assigns PP3 for c.373A>C with aGVGD Class C35 and BayesDel score 0.576078, while SpliceAI predicts no significant splice impact with a max delta score of 0.09.
No criteria match.
Met · 3
PS3 StrongTP53 functional evidence supports a damaging effect. In the TP53 VCEP functional worksheet, p.(Thr125Pro) is listed as non-functional in Kato data and loss-of-function in additional eligible assays, with a pre-assigned PS3 code. This is consistent with a deleterious effect on TP53 protein function. Details ▾Hide ▴
Rule
TP53 VCEP PS3_Strong: non-functional on Kato data and loss of function by the majority of other eligible assays.
Evidence considered
- Functional worksheet row: T125P | NA | Non-functional | NA | LOF | LOF | NA | PS3
- OncoKB: Likely Oncogenic
- biological effect: Likely Loss-of-function
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesoncokb ↗PMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1. Its observed population frequency is therefore below the TP53 VCEP PM2_Supporting threshold of less than 0.00003 overall and below the per-ancestry multiple-allele threshold of less than 0.00004. Details ▾Hide ▴
Rule
TP53 VCEP PM2 is applied at Supporting strength for allele frequency <0.00003 overall, with additional ancestry-specific constraints.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
Sources
PP3 SupportingTP53 in silico evidence supports a deleterious effect. In the TP53 VCEP PP3/BP4 worksheet, c.373A>C is assigned PP3 with aGVGD Class C35 and BayesDel score 0.576078. SpliceAI predicts no significant splice impact with a max delta score of 0.09, so the evidence supports a missense damaging effect rather than a splice-driven benign interpretation. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for missense variants is assigned using the PP3/BP4 worksheet and flowchart.
Evidence considered
- PP3-BP4 worksheet row: c.373A>C | p.Thr125Pro | Class C35 | 0.576078 | PP3 | 0.09
- SpliceAI max delta score = 0.09
Sources
Not met · 5 · evaluated, threshold not reached
PS1 No alternate nucleotide change producing the same p.(Thr125Pro) amino acid substitution was identified from the reviewed germline database evidence, so PS1 is not met. Details ▾Hide ▴
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its frequency is below the TP53 VCEP BA1 threshold of at least 0.001 in a qualifying ancestry group. BA1 is not met. Details ▾Hide ▴
Rule
TP53 VCEP 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 frequency is below the TP53 VCEP BS1 threshold of at least 0.0003 in a qualifying ancestry group. BS1 is not met. Details ▾Hide ▴
Rule
TP53 VCEP 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 retained TP53 function. The TP53 VCEP functional worksheet assigns PS3, not BS3, because p.(Thr125Pro) is non-functional and shows loss of function in eligible assays. Details ▾Hide ▴
Rule
TP53 VCEP BS3 requires retained or partially retained function without loss of function across eligible assays.
Evidence considered
- Functional worksheet row assigns PS3 for T125P
- Kato result: Non-functional
- Additional eligible assays: LOF
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
BP4 Available in silico evidence does not support a benign interpretation. The TP53 VCEP PP3/BP4 worksheet assigns PP3, not BP4, for c.373A>C, and the BayesDel score of 0.576078 is well above the benign thresholds. SpliceAI predicts no significant splice effect, with a max delta score of 0.09. Details ▾Hide ▴
Rule
TP53 VCEP BP4 requires qualifying benign BayesDel and splicing predictions.
Evidence considered
- PP3-BP4 worksheet row assigns PP3
- BayesDel score = 0.576078
- SpliceAI max delta score = 0.09
Sources
Not assessed · 8 · no assessment recorded
PS2 No de novo data, confirmed parentage, or proband cancer-point information were identified, so PS2 cannot be assessed. Details ▾Hide ▴
Rule
TP53 VCEP PS2 strength is assigned by proband point totals for de novo occurrences.
Evidence considered
- No de novo evidence identified in the reviewed materials
Still missing
- Documented de novo status with confirmed maternity and paternity
- Proband cancer history with TP53 VCEP point assignment
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS4 The variant meets the population prerequisite for PS4 because it is absent from gnomAD, but no scored proband observations with Li-Fraumeni syndrome-associated cancers were identified. Available evidence is insufficient to assign a TP53 PS4 point total. Details ▾Hide ▴
Rule
TP53 VCEP PS4 is point-based and requires PM2_Supporting first.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- No PS4 point-scored proband data identified
Still missing
- Proband-level TP53-associated cancer observations
- PS4 point total using the TP53 VCEP cancer scoring table
Sources
PM1 Cancer Hotspots review did not confirm the exact variant or residue-level evidence needed to verify TP53 hotspot thresholds. Therefore, the somatic hotspot evidence required for PM1 was not established from the reviewed materials. Details ▾Hide ▴
Rule
TP53 VCEP PM1 applies to specified hotspot codons or to variants with qualifying Cancer Hotspots somatic counts for the same amino acid change.
Evidence considered
- Hotspot assessment status: uncertain
- Exact variant listing in Cancer Hotspots: uncertain
Still missing
- Verified Cancer Hotspots residue row and exact amino acid change count
Sources
PM5 Other missense substitutions at codon 125 are reported in ClinVar, but the reviewed evidence did not establish that these alternate changes were previously classified as Pathogenic or Likely Pathogenic under TP53 VCEP specifications. PM5 therefore remains unassessed. Details ▾Hide ▴
Rule
TP53 VCEP PM5 requires prior pathogenic or likely pathogenic missense changes at the same residue under TP53 VCEP specifications.
Evidence considered
- ClinVar includes other codon 125 substitutions such as p.(Thr125Arg) and p.(Thr125Lys)
Still missing
- Verified TP53 VCEP-based classifications for other pathogenic missense changes at residue Thr125
Sources
PP1 No segregation data were identified, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
TP53 VCEP PP1 is based on counted cosegregation meioses.
Evidence considered
- No segregation evidence identified
Still missing
- Family segregation data with counted informative meioses
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP4 No low-variant-allele-fraction blood finding or other qualifying constitutional mosaicism evidence was identified, so PP4 cannot be assessed. Details ▾Hide ▴
Rule
TP53 VCEP PP4 is applied to qualifying low-VAF constitutional mosaicism observations.
Evidence considered
- No qualifying PP4 VAF data identified
Still missing
- Observed blood VAF and confirmation of constitutional mosaicism context
Sources
BS2 No source documenting unaffected older female carriers was identified, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
TP53 VCEP BS2 is based on counts of unaffected older female carriers from a single source.
Evidence considered
- No qualifying BS2 carrier dataset identified
Still missing
- Single-source count of unrelated females aged at least 60 years without cancer who carry the variant
Sources
BS4 No lack-of-segregation evidence in affected relatives with Li-Fraumeni syndrome-associated cancers was identified, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
TP53 VCEP BS4 requires lack of segregation in affected relatives with qualifying cancers.
Evidence considered
- No family non-segregation data identified
Still missing
- Documented non-segregation in affected family members
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.(Thr125Pro), and does not fall into the TP53 PVS1 null-variant categories for nonsense, frameshift, canonical +/-1,2 splice, initiation codon, or qualifying exon-level loss. Available evidence does not support application of PVS1. Details ▾Hide ▴
Rule
TP53 VCEP PVS1 applies to qualifying null variants per the TP53-specific PVS1 flowchart.
Evidence considered
- NM_000546.6:c.373A>C encodes p.(Thr125Pro)
- Variant-level PVS1 scaffold places this variant in the 'other' bucket
- Canonical splice consensus status: false
Sources
PM3 N/APM3 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per TP53 VCEP.
Evidence considered
- TP53 VCEP lists PM3 as not applicable
Sources
PM4 N/APM4 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per TP53 VCEP.
Evidence considered
- TP53 VCEP lists PM4 as not applicable
Sources
PM6 N/APM6 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per TP53 VCEP.
Evidence considered
- TP53 VCEP lists PM6 as not applicable
Sources
PP2 N/APP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per TP53 VCEP.
Evidence considered
- TP53 VCEP lists PP2 as not applicable
Sources
PP5 N/APP5 is not for use in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per TP53 VCEP.
Evidence considered
- TP53 VCEP lists PP5 as not applicable
Sources
BP1 N/ABP1 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per TP53 VCEP.
Evidence considered
- TP53 VCEP lists BP1 as not applicable
Sources
BP2 N/ABP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per TP53 VCEP.
Evidence considered
- TP53 VCEP lists BP2 as not applicable
Sources
BP3 N/ABP3 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per TP53 VCEP.
Evidence considered
- TP53 VCEP lists BP3 as not applicable
Sources
BP5 N/ABP5 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per TP53 VCEP.
Evidence considered
- TP53 VCEP lists BP5 as not applicable
Sources
BP6 N/ABP6 is not for use in the TP53 VCEP framework. Details ▾Hide ▴
Rule
Not applicable per TP53 VCEP.
Evidence considered
- TP53 VCEP lists BP6 as not applicable
Sources
BP7 N/ABP7 is intended for synonymous or certain intronic variants without predicted splice impact and does not apply to this missense variant. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to qualifying synonymous or intronic variants.
Evidence considered
- Variant type: missense
- SpliceAI max delta score = 0.09
Sources
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.6
- Coding (HGVS c.)
- NM_000546.6:c.373A>C
- Protein (HGVS p.)
- NP_000537.3:p.(Thr125Pro)
- GRCh38
- chr17:7675996 T>G
- GRCh37
- chr17:7579314 T>G
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
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 SupportingTP53 in silico evidence supports a deleterious effect. In the TP53 VCEP PP3/BP4 worksheet, c.373A>C is assigned PP3 with aGVGD Class C35 and BayesDel score 0.576078. SpliceAI predicts no significant splice impact with a max delta score of 0.09, so the evidence supports a missense damaging effect rather than a splice-driven benign interpretation. Details ▾Hide ▴
Rule
TP53 VCEP PP3 for missense variants is assigned using the PP3/BP4 worksheet and flowchart.
Evidence considered
- PP3-BP4 worksheet row: c.373A>C | p.Thr125Pro | Class C35 | 0.576078 | PP3 | 0.09
- SpliceAI max delta score = 0.09
Sources
BP4 Available in silico evidence does not support a benign interpretation. The TP53 VCEP PP3/BP4 worksheet assigns PP3, not BP4, for c.373A>C, and the BayesDel score of 0.576078 is well above the benign thresholds. SpliceAI predicts no significant splice effect, with a max delta score of 0.09. Details ▾Hide ▴
Rule
TP53 VCEP BP4 requires qualifying benign BayesDel and splicing predictions.
Evidence considered
- PP3-BP4 worksheet row assigns PP3
- BayesDel score = 0.576078
- SpliceAI max delta score = 0.09
Sources
BP7 N/ABP7 is intended for synonymous or certain intronic variants without predicted splice impact and does not apply to this missense variant. Details ▾Hide ▴
Rule
TP53 VCEP BP7 applies to qualifying synonymous or intronic variants.
Evidence considered
- Variant type: missense
- SpliceAI max delta score = 0.09
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).
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/variation/376666/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7579314-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7675996-T-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.373A…
- OncoKB ↗www.oncokb.org/gene/TP53/T125P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104422741
- 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 Likely pathogenic (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).
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; COSV52951418, n = 8 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.