About TP53
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TP53 c.374C>T, p.(Thr125Met)
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
PM2Supporting
PM2 · supporting
This variant is rare in population databases. In gnomAD v4.1, the total allele frequency is 1.86088e-06 (3/1612144), which is below the TP53 VCEP PM2 threshold of 0.00003, and no ancestry group shows multiple alleles above 0.00004; PM2_Supporting is met.
PP3Moderate
PP3 · moderate
For this missense variant, the TP53 VCEP bioinformatic worksheet assigns PP3_moderate. The worksheet lists aGVGD Class C65 and BayesDel 0.500232, which is above the TP53 VCEP PP3 threshold of 0.16. REVEL is also high at 0.925, while SpliceAI predicts no significant splice effect (max delta score 0.09).
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: PM2 supporting (+1) + PP3 moderate (+2) = 3 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
3 / 1,612,144 alleles
gnomAD v4.1: 3 / 1,612,144 alleles. Recorded AF 1.86088e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18471e-05; MAF= 0.00318%, 1/31400 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114758; MAF= 0.01148%, 1/8714 alleles, homozygotes = 0).
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 identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
No listed criterion applied
OncoKB ↗
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: 2 met · 6 not met · 9 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.374C>T (p.Thr125Met) variant has been reported in ClinVar, where most submissions classify it as likely pathogenic or pathogenic.
This variant is rare in population databases, with gnomAD v4.1 showing an allele frequency of 1.86088e-06 (3/1612144) and a highest observed African/African American frequency of 1.33568e-05, which is below the TP53 VCEP PM2_Supporting threshold of 0.00003.
In the TP53 VCEP functional worksheet, p.Thr125Met is listed as non-functional in Kato et al. but as no loss of function in other eligible assays, leading to a preassigned interpretation of "No evidence" rather than PS3 or BS3.
TP53 VCEP computational evidence supports pathogenicity at the PP3_moderate level, with aGVGD Class C65 and BayesDel 0.500232 in the TP53 worksheet; REVEL is 0.925, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.09.
No criteria match.
Met · 2
PM2 SupportingThis variant is rare in population databases. In gnomAD v4.1, the total allele frequency is 1.86088e-06 (3/1612144), which is below the TP53 VCEP PM2 threshold of 0.00003, and no ancestry group shows multiple alleles above 0.00004; PM2_Supporting is met. Details ▾Hide ▴
Rule
TP53 VCEP PM2_Supporting: AF < 0.00003 and no ancestry group with multiple alleles at AF > 0.00004
Evidence considered
- gnomAD v4.1 total AF 1.86088e-06
- African/African American AF 1.33568e-05
- grpmax FAF 2.8e-07.
- gnomAD v2.1 total AF 3.18471e-05 with 1 allele overall
- no conflicting higher-frequency ancestry signal with multiple alleles was identified.
Sources
PP3 ModerateFor this missense variant, the TP53 VCEP bioinformatic worksheet assigns PP3_moderate. The worksheet lists aGVGD Class C65 and BayesDel 0.500232, which is above the TP53 VCEP PP3 threshold of 0.16. REVEL is also high at 0.925, while SpliceAI predicts no significant splice effect (max delta score 0.09). Details ▾Hide ▴
Rule
TP53 VCEP PP3_Moderate for missense variants with aGVGD C65 and BayesDel >= 0.16
Evidence considered
- PP3-BP4 worksheet row: c.374C>T | p.Thr125Met | Class C65 | 0.500232 | PP3_moderate | 0.09.
- REVEL score 0.925.
- SpliceAI max delta 0.09.
Sources
Not met · 6 · evaluated, threshold not reached
PVS1 This missense variant, NM_000546.6:c.374C>T (p.Thr125Met), is not a nonsense, frameshift, canonical +/-1,2 splice, or other TP53 null variant under the TP53 VCEP PVS1 framework, so PVS1 is not applied. Details ▾Hide ▴
Rule
TP53 VCEP PVS1 flowchart for null variants
Evidence considered
- TP53 is PVS1-eligible at the gene level
- but the variant-specific assessment identifies this change as outside the null-variant buckets.
- Protein consequence is p.(Thr125Met)
- a missense substitution.
Sources
PS3 In the TP53 VCEP functional worksheet, p.Thr125Met is listed as non-functional in Kato et al. but as no loss of function in other eligible assays, with an overall preassigned interpretation of "No evidence"; therefore the available functional data do not meet TP53 PS3. Details ▾Hide ▴
Rule
TP53 VCEP PS3 functional assay framework
Evidence considered
- Functional worksheet row: T125M | NA | Non-functional | NA | noLOF | noLOF | NA | No evidence.
- TP53 VCEP PS3 requires non-functional Kato data plus loss of function in the majority of other eligible assays.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
BA1 This variant does not meet the TP53 VCEP BA1 threshold. In gnomAD v4.1, the highest observed filtering allele frequency is far below the BA1 cutoff of 0.001, so stand-alone benign evidence is not met. Details ▾Hide ▴
Rule
TP53 VCEP BA1 requires FAF >= 0.001 in a qualifying continental population
Evidence considered
- gnomAD v4.1 total AF 1.86088e-06
- grpmax FAF 2.8e-07.
Sources
BS1 This variant does not meet the TP53 VCEP BS1 threshold. The highest observed allele frequency in gnomAD is below the BS1 cutoff of 0.0003, and the available data do not show the required qualifying frequency signal in a continental ancestry group. Details ▾Hide ▴
Rule
TP53 VCEP BS1 requires FAF >= 0.0003 and < 0.001 in a qualifying continental population
Evidence considered
- gnomAD v4.1 African/African American AF 1.33568e-05.
- gnomAD v2.1 African/African American AF 0.000114758 with a single observed allele.
Sources
BS3 Available functional evidence does not support retained TP53 function. In the TP53 VCEP functional worksheet, p.Thr125Met is not assigned BS3 and is instead summarized as "No evidence," because the reviewed assays do not provide the consistent retained-function pattern required for BS3. Details ▾Hide ▴
Rule
TP53 VCEP BS3 functional assay framework
Evidence considered
- Functional worksheet row for T125M ends with preassigned code: No evidence.
- TP53 VCEP BS3 requires retained or partially retained function across eligible assays under the specified framework.
Sources
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
BP4 Benign computational evidence is not met. The TP53 VCEP bioinformatic worksheet assigns PP3_moderate rather than BP4, with BayesDel 0.500232, which is above the benign BP4 range, and REVEL is high at 0.925. SpliceAI predicts no significant splice effect (max delta score 0.09), but the missense prediction profile supports pathogenic rather than benign computational evidence. Details ▾Hide ▴
Rule
TP53 VCEP BP4 missense rule requires BayesDel < 0.16 with no predicted splice effect; BP4_Moderate requires BayesDel <= -0.008 and no predicted splice effect
Evidence considered
- BayesDel 0.500232.
- REVEL 0.925.
- SpliceAI max delta 0.09.
- PP3-BP4 worksheet preassigns PP3_moderate.
Sources
Not assessed · 9 · no assessment recorded
PS1 No reviewed evidence identified a different nucleotide change causing the same amino acid substitution with a prior TP53 VCEP pathogenic or likely pathogenic classification, so PS1 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP PS1 requires the same amino acid change as a TP53 VCEP-classified pathogenic or likely pathogenic variant
Evidence considered
- ClinVar review confirmed the exact c.374C>T variant but did not establish a PS1-eligible alternate nucleotide match.
Still missing
- Residue-level review for previously classified alternate nucleotide changes encoding p.Thr125Met was not available in the reviewed sources.
Sources
PS2 No confirmed de novo observations with parentage and TP53-relevant phenotype documentation were identified, so PS2 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP PS2 point-based de novo framework
Evidence considered
- TP53 VCEP PS2 uses a point-based de novo framework
- but no qualifying case-level data were available.
Still missing
- Confirmed maternity/paternity data were not identified.
- No scored de novo proband observations were identified.
Sources
cspec ↗vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS4 Although PM2_Supporting is met, no reviewed evidence established the number of unrelated affected individuals needed to score TP53 PS4, so PS4 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP PS4 point-based affected-individual framework
Evidence considered
- TP53 VCEP PS4 requires point-based affected-individual evidence and depends on PM2_Supporting first.
- Population data support rarity
- but affected-case counts were not established.
Still missing
- No TP53 PS4 point tally from unrelated affected probands was identified.
- Phenotype-specific affected-case data were not available for scoring.
Sources
PM1 Codon 125 is not one of the TP53 VCEP predefined PM1 hotspot codons, and the available Cancer Hotspots review for p.Thr125Met was uncertain rather than confirmed at the exact variant level, so PM1 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP PM1 hotspot criteria
Evidence considered
- TP53 VCEP predefined hotspot codons are 175
- 245
- 248
- 249
- 273
- and 282.
- Cancer Hotspots review for T125M was marked uncertain and needs human review.
Still missing
- Verified Cancer Hotspots exact amino acid change count was not established from the reviewed materials.
Sources
PM5 No reviewed source established one or more different TP53 VCEP-classified pathogenic or likely pathogenic missense variants at residue Thr125, so PM5 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP PM5 residue-based framework
Evidence considered
- Reviewed materials confirmed the exact variant but did not establish PM5-eligible alternate missense changes at the same residue.
Still missing
- Residue-specific review for other TP53 VCEP-classified missense changes at codon 125 was not available in the reviewed materials.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP PP1 meiosis-based segregation framework
Evidence considered
- TP53 VCEP PP1 requires cosegregation across informative meioses
- which was not available.
Still missing
- No informative pedigrees or 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 data or phenotype-specific mosaicism evidence were identified, so the TP53-specific PP4 rule was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP PP4 low-VAF observation framework
Evidence considered
- TP53 VCEP PP4 is based on low-level blood VAF observations suggestive of constitutional mosaicism
- which were not available.
Still missing
- No variant allele fraction data in the 5-35% range were identified.
- No qualifying TP53 phenotype context for this rule was identified.
Sources
BS2 No single-source cohort data identified 2 or more unrelated women aged 60 years or older without cancer who carry this variant, so BS2 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP BS2 unaffected older female carrier framework
Evidence considered
- TP53 VCEP BS2 requires unaffected older female carriers from a single source
- which were not available.
Still missing
- No qualifying unaffected older-carrier cohort was identified.
Sources
BS4 No lack-of-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
TP53 VCEP BS4 non-segregation framework
Evidence considered
- TP53 VCEP BS4 requires documented lack of segregation in affected relatives
- which was not available.
Still missing
- No informative family data showing non-segregation with TP53-associated disease were identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is not applicable in the TP53 VCEP framework for this gene. Details ▾Hide ▴
Rule
TP53 VCEP applicability table
Evidence considered
- TP53 VCEP marks PM3 as not applicable.
Sources
PM4 N/APM4 is not applicable for this TP53 missense variant under the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP applicability table
Evidence considered
- TP53 VCEP marks PM4 as not applicable.
Sources
PM6 N/APM6 is not applicable in the TP53 VCEP framework for this gene. Details ▾Hide ▴
Rule
TP53 VCEP applicability table
Evidence considered
- TP53 VCEP marks PM6 as not applicable.
Sources
PP2 N/APP2 is not applicable in the TP53 VCEP framework for this gene. Details ▾Hide ▴
Rule
TP53 VCEP applicability table
Evidence considered
- TP53 VCEP marks PP2 as not applicable.
Sources
PP5 N/APP5 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP applicability table
Evidence considered
- TP53 VCEP marks PP5 as not applicable.
Sources
BP1 N/ABP1 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP applicability table
Evidence considered
- TP53 VCEP marks BP1 as not applicable.
Sources
BP2 N/ABP2 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP applicability table
Evidence considered
- TP53 VCEP marks BP2 as not applicable.
Sources
BP3 N/ABP3 is not applicable for this TP53 variant under the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP applicability table
Evidence considered
- TP53 VCEP marks BP3 as not applicable.
Sources
BP5 N/ABP5 is not applicable in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP applicability table
Evidence considered
- TP53 VCEP marks BP5 as not applicable.
Sources
BP6 N/ABP6 is not used in the TP53 VCEP framework. Details ▾Hide ▴
Rule
TP53 VCEP applicability table
Evidence considered
- TP53 VCEP marks BP6 as not applicable.
Sources
BP7 N/ABP7 does not apply because this is a missense variant rather than a synonymous or qualifying intronic change. Details ▾Hide ▴
Rule
TP53 VCEP BP7 silent/intronic rule
Evidence considered
- Protein consequence is p.(Thr125Met).
- BP7 in TP53 VCEP is limited to synonymous or qualifying intronic variants.
Sources
Identifiers
- Gene
- TP53
- Transcript
- NM_000546.6
- Coding (HGVS c.)
- NM_000546.6:c.374C>T
- Protein (HGVS p.)
- NP_000537.3:p.(Thr125Met)
- GRCh38
- chr17:7675995 G>A
- GRCh37
- chr17:7579313 G>A
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
3 / 1,612,144 alleles
AF 1.86e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
1 / 31,400 alleles
AF 3.18e-05 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,612,144 alleles · 0 hom · FAF 2.8e-07
| African/African American1 / 74,868 | 1.3e-05 |
| European (non-Finnish)2 / 1,180,036 | 1.7e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 3.2e-05 · 1 / 31,400 alleles · 0 hom
| African/African American1 / 8,714 | 0.00011 |
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.86088e-06; MAF= 0.00019%, 3/1612144 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33568e-05; MAF= 0.00134%, 1/74868 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18471e-05; MAF= 0.00318%, 1/31400 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114758; MAF= 0.01148%, 1/8714 alleles, homozygotes = 0).
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 worksheet lists aGVGD Class C65 and BayesDel 0.500232, which is above the TP53 VCEP PP3 threshold of 0.16. REVEL is also high at 0.925, while SpliceAI predicts no significant splice effect (max delta score 0.09). Details ▾Hide ▴
Rule
TP53 VCEP PP3_Moderate for missense variants with aGVGD C65 and BayesDel >= 0.16
Evidence considered
- PP3-BP4 worksheet row: c.374C>T | p.Thr125Met | Class C65 | 0.500232 | PP3_moderate | 0.09.
- REVEL score 0.925.
- SpliceAI max delta 0.09.
Sources
BP4 Benign computational evidence is not met. The TP53 VCEP bioinformatic worksheet assigns PP3_moderate rather than BP4, with BayesDel 0.500232, which is above the benign BP4 range, and REVEL is high at 0.925. SpliceAI predicts no significant splice effect (max delta score 0.09), but the missense prediction profile supports pathogenic rather than benign computational evidence. Details ▾Hide ▴
Rule
TP53 VCEP BP4 missense rule requires BayesDel < 0.16 with no predicted splice effect; BP4_Moderate requires BayesDel <= -0.008 and no predicted splice effect
Evidence considered
- BayesDel 0.500232.
- REVEL 0.925.
- SpliceAI max delta 0.09.
- PP3-BP4 worksheet preassigns PP3_moderate.
Sources
BP7 N/ABP7 does not apply because this is a missense variant rather than a synonymous or qualifying intronic change. Details ▾Hide ▴
Rule
TP53 VCEP BP7 silent/intronic rule
Evidence considered
- Protein consequence is p.(Thr125Met).
- BP7 in TP53 VCEP is limited to synonymous or qualifying intronic variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.925. BayesDel score = 0.500232.
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
3 / 1,612,144 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/183748/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-7579313-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-7675995-G-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000546.6%3Ac.374C…
- OncoKB ↗www.oncokb.org/gene/TP53/T125M
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104356960
- 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= 1.86088e-06; MAF= 0.00019%, 3/1612144 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33568e-05; MAF= 0.00134%, 1/74868 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18471e-05; MAF= 0.00318%, 1/31400 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114758; MAF= 0.01148%, 1/8714 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (11 clinical laboratories) and as Pathogenic (3 clinical laboratories) and as Likely Pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.925. BayesDel score = 0.500232.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52673504, n = 57 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.