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LYFE SCIENCES
Project: HERA
NM_000546.6:c.373A>C
p.Thr125Pro  ·  TP53
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Classification rationale
1

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.

oncokb ↗ clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

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

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.

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
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52951418, n = 8 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueT125
Hotspots ↗