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
Final classification
Likely Pathogenic
PS3PM2PP3
TP53
c.373A>C
p.Thr125Pro
This variant
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 ↗
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 · 3 applied · 13 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
Pathogenic
TP53 functional evidence supports a damaging effect. In the TP53 VCEP functional worksheet, p.(Thr125Pro) is listed as non-functional in Kato data and loss-of-function in additional eligible assays, with a pre-assigned PS3 code. This is consistent with a deleterious effect on TP53 protein function.
Functional worksheet row: T125P | NA | Non-functional | NA | LOF | LOF | NA | PS3OncoKB: Likely Oncogenicbiological effect: Likely Loss-of-function
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1. Its observed population frequency is therefore below the TP53 VCEP PM2_Supporting threshold of less than 0.00003 overall and below the per-ancestry multiple-allele threshold of less than 0.00004.
gnomAD v2.1: absentgnomAD v4.1: absent
PP3
supporting
Pathogenic
TP53 in silico evidence supports a deleterious effect. In the TP53 VCEP PP3/BP4 worksheet, c.373A>C is assigned PP3 with aGVGD Class C35 and BayesDel score 0.576078. SpliceAI predicts no significant splice impact with a max delta score of 0.09, so the evidence supports a missense damaging effect rather than a splice-driven benign interpretation.
PP3-BP4 worksheet row: c.373A>C | p.Thr125Pro | Class C35 | 0.576078 | PP3 | 0.09SpliceAI max delta score = 0.09
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
PS1
No alternate nucleotide change producing the same p.(Thr125Pro) amino acid substitution was identified from the reviewed germline database evidence, so PS1 is not met.
PS2
No de novo data, confirmed parentage, or proband cancer-point information were identified, so PS2 cannot be assessed.
PS4
The variant meets the population prerequisite for PS4 because it is absent from gnomAD, but no scored proband observations with Li-Fraumeni syndrome-associated cancers were identified.
PM1
Cancer Hotspots review did not confirm the exact variant or residue-level evidence needed to verify TP53 hotspot thresholds.
PM5
Other missense substitutions at codon 125 are reported in ClinVar, but the reviewed evidence did not establish that these alternate changes were previously classified as Pathogenic or Likely Pathogenic under TP53 VCEP specifications.
PP1
No segregation data were identified, so PP1 cannot be assessed.
PP4
No low-variant-allele-fraction blood finding or other qualifying constitutional mosaicism evidence was identified, so PP4 cannot be assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its frequency is below the TP53 VCEP BA1 threshold of at least 0.001 in a qualifying ancestry group.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its frequency is below the TP53 VCEP BS1 threshold of at least 0.0003 in a qualifying ancestry group.
BS2
No source documenting unaffected older female carriers was identified, so BS2 cannot be assessed.
BS3
Available functional evidence does not support retained TP53 function.
BS4
No lack-of-segregation evidence in affected relatives with Li-Fraumeni syndrome-associated cancers was identified, so BS4 cannot be assessed.
BP4
Available in silico evidence does not support a benign interpretation.
N/A · 12
PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7
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.
Understanding the function-structure and function-mutation relationships of p53
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Mutational processes shape the landscape of TP53 mutations in human cancer.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links