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LYFE SCIENCES
Project: HERA
NM_000546.6:c.374C>T
p.Thr125Met  ·  TP53
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Classification rationale
1

The TP53 c.374C>T (p.Thr125Met) variant has been reported in ClinVar, where most submissions classify it as likely pathogenic or pathogenic.

clinvar ↗
2

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.

gnomad_v4 ↗ cspec ↗
3

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.

PMID:12826609 ↗ PMID:29979965 ↗ PMID:30224644 ↗
4

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Inconclusive
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.925. BayesDel score = 0.500232.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52673504, n = 57 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueT125
Hotspots ↗