The TP53 c.374C>T (p.Thr125Met) variant has been reported in ClinVar, where most submissions classify it as likely pathogenic or pathogenic.1 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 0.00003.2 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 BS3.3 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 0.09.4
Final classification
VUS
PM2PP3
TP53
c.374C>T
p.Thr125Met
This variant
The TP53 c.374C>T (p.Thr125Met) variant has been reported in ClinVar, where most submissions classify it as likely pathogenic or pathogenic.
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.
Classification rationale
PM2PP3
VUS
TP53 c.374C>T
PM2 + PP3
→
VUS
3
vcep_functional_worksheetPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
4
vcep_pp3_bp4_codesbayesdelrevelspliceai ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
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.
Gene diagram
· NM_000546.6 · variants mapped to exon structure
TP53
NM_000546.6
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
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.
gnomAD v4.1 total AF 1.86088e-06African/African American AF 1.33568e-05grpmax FAF 2.8e-07.
PP3
moderate
Pathogenic
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).
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.
Assessed · not applied
· 6 not met · 9 not assessed
Pathogenic
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.
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.
PS2
No confirmed de novo observations with parentage and TP53-relevant phenotype documentation were identified, so PS2 was not assessed.
PS3
In the TP53 VCEP functional worksheet, p.Thr125Met is listed as non-functional in Kato et al.
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.
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.
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.
PP1
No segregation data were identified for this variant, so PP1 was not assessed.
PP4
No blood variant allele fraction data or phenotype-specific mosaicism evidence were identified, so the TP53-specific PP4 rule was not assessed.
Benign
BA1
This variant does not meet the TP53 VCEP BA1 threshold.
BS1
This variant does not meet the TP53 VCEP BS1 threshold.
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.
BS3
Available functional evidence does not support retained TP53 function.
BS4
No lack-of-segregation data were identified for this variant, so BS4 was not assessed.
BP4
Benign computational evidence is not met.
N/A · 11
PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,612,144
0 hom · FAF 2.8e-05%
0 hom · FAF 2.8e-05%
African/African American 1 / 74,868 |
0.0013% |
European (non-Finnish) 2 / 1,180,036 |
0.00017% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0032%
· 1 / 31,400
0 hom
0 hom
African/African American 1 / 8,714 |
0.011% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
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
Inconclusive
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52673504, n = 57 times).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links