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
TP53
Final classification
VUS
TP53 c.374C>T · p.Thr125Met
TP53
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
Gene diagram
· NM_000546.6 · variants mapped to exon structure
TP53
NM_000546.6
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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