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.1 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 0.00003.2 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 PS3.3 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 0.09.4
TP53
Final classification
Likely Pathogenic
TP53 c.373A>C · p.Thr125Pro
TP53
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.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PS3 strong (+4) + PM2 supporting (+1) + PP3 supporting (+1) = 6 points, which maps to Likely Pathogenic.
Classification rationale
PS3PM2PP3
Likely Pathogenic
TP53 c.373A>C
PS3 + PM2 + PP3
→
Likely Pathogenic
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗
4
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7spliceai ↗
Gene diagram
· NM_000546.6 · variants mapped to exon structure
TP53
NM_000546.6
Fetching transcript structure from UCSC…
Applied criteria · 3 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 · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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; COSV52951418, n = 8 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:12826609
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:29979965
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:30224644
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links