LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-19
Case ID: NM_000546.6_c.925C_T_20260519_003439
Framework: None
Variant classification summary

TP53  · NP_000537.3:p.(Pro309Ser)  · NM_000546.6
GRCh37: chr17:7576921 G>A  ·  GRCh38: chr17:7673603 G>A
Gene: TP53 Transcript: NM_000546.6
Final call
All criteria require review: For research and educational purposes only.
Variant details
Gene
TP53
Transcript
NM_000546.6
Protein
NP_000537.3:p.(Pro309Ser)
gnomAD AF
6.195310893091237e-07 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The TP53 c.925C>T (p.Pro309Ser; p.P309S) variant has been observed in somatic cancers in COSMIC (COSV52729434; n=5) and has been reported in ClinVar with predominantly uncertain significance submissions and one likely benign submission.
2
This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1614124 alleles; AF 6.19531e-07), which is below the TP53 VCEP PM2_Supporting threshold of 0.00003.
3
In TP53 functional studies curated by the VCEP, Kato transactivation testing classified p.Pro309Ser as functional and Giacomelli data showed no loss of function, supporting BS3.
4
Computational evidence predicts no splice effect (SpliceAI max delta score 0.00), and the TP53 VCEP bioinformatic worksheet assigns BP4 for c.925C>T with BayesDel 0.138442; REVEL 0.607 was available but does not override the TP53-specific computational rule.
Final determination:
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PP5 N/A This criterion is not used in the TP53 VCEP specification.
cspec
PP4 Not assessed No constitutional mosaicism data or blood variant allele fraction observations in the 5-35% range were identified, so TP53-specific PP4 could not be assessed.
cspec
PS4 Not assessed PM2_Supporting is met, but no proband-level Li-Fraumeni syndrome cancer point data were identified to score PS4 under the TP53 VCEP point system.
cspec vcep_ps4_points_table
BP3 N/A This criterion is not applicable in the TP53 VCEP specification.
cspec
BP1 N/A This criterion is not applicable in the TP53 VCEP specification.
cspec
BS1 Not met The population frequency does not meet the TP53 VCEP BS1 threshold. In gnomAD v4.1, this variant is present at 1/1614124 alleles (AF 6.19531e-07), which is below the BS1 cutoff of 0.0003, and no qualifying subpopulation frequency was identified.
gnomad_v4 cspec
BP6 N/A This criterion is not used in the TP53 VCEP specification.
cspec
PM1 Not met This missense variant is not in one of the TP53 hotspot codons eligible for PM1 by rule, and no Cancer Hotspots evidence was identified to confirm the same amino acid change as a qualifying somatic hotspot. COSMIC shows 5 somatic observations, but that alone does not satisfy the TP53 VCEP PM1 requirement.
cspec hotspots
BP7 N/A BP7 applies to synonymous or relevant intronic variants, and this is a missense variant.
cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PVS1 N/A This variant is a missense substitution and does not fall into the TP53 PVS1 null-variant or canonical splice-variant framework. The generic PVS1 scaffold also indicates that it is not a nonsense, frameshift, or canonical ±1,2 splice variant.
cspec vcep_pvs1_flowchart pvs1_gene_context pvs1_variant_assessment
PS2 Not assessed No confirmed de novo observations with the cancer-point information required by the TP53 VCEP were identified.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2 N/A This criterion is not applicable in the TP53 VCEP specification.
cspec
BP2 N/A This criterion is not applicable in the TP53 VCEP specification.
cspec
PS1 Not assessed No previously established TP53 VCEP pathogenic or likely pathogenic variant producing the same amino acid change was identified from the available evidence.
cspec clinvar
PM3 N/A This criterion is not applicable in the TP53 VCEP specification.
cspec
BA1 Not met The population frequency is far below the TP53 VCEP BA1 threshold. In gnomAD v4.1, this variant is present at 1/1614124 alleles (AF 6.19531e-07), which is below the BA1 cutoff of 0.001.
gnomad_v4 cspec
PM6 N/A This criterion is not applicable in the TP53 VCEP specification.
cspec
BS4 Not assessed No family segregation data were identified to assess lack of segregation with Li-Fraumeni syndrome-associated cancers.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PM5 Not assessed TP53 uses classic same-residue missense PM5 logic, but no previously established TP53 VCEP pathogenic or qualifying likely pathogenic comparator at codon 309 was identified from the available evidence.
cspec pm5_candidates
BS3 Met In the TP53 VCEP functional worksheet, p.Pro309Ser is classified as functional in the Kato transactivation assay and shows no loss of function in Giacomelli functional data. This pattern supports a benign functional effect and meets BS3 under the TP53 VCEP rules.
vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:30224644
PM2 Met This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1614124 alleles; AF 6.19531e-07). This frequency is below the TP53 VCEP PM2_Supporting threshold of 0.00003, and no qualifying non-founder subpopulation has multiple alleles above the 0.00004 threshold.
gnomad_v2 gnomad_v4 cspec
PP3 Not met Available computational evidence does not meet the TP53 VCEP PP3 threshold. BayesDel is 0.138442, which is below the PP3 cutoff of 0.16, and SpliceAI predicts no splice effect (max delta score 0.00). REVEL is 0.607, but TP53 missense PP3/BP4 assignment is governed by the TP53-specific BayesDel/aGVGD plus SpliceAI framework, and the precomputed TP53 worksheet does not assign PP3 for c.925C>T.
bayesdel spliceai revel vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 cspec
BP5 N/A This criterion is not applicable in the TP53 VCEP specification.
cspec
PP1 Not assessed No segregation data were identified to assess cosegregation with Li-Fraumeni syndrome-associated cancers.
cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP4 Met Computational evidence supports a benign effect. The TP53 VCEP bioinformatic worksheet assigns BP4 for c.925C>T with BayesDel 0.138442, which is below 0.16, and SpliceAI predicts no splice effect (max delta score 0.00, below the 0.2 splice-impact threshold and within the <=0.1 no-splice-impact range). REVEL is 0.607, but the TP53-specific computational framework supports BP4 for this variant.
bayesdel spliceai revel vcep_pp3_bp4_codes vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 cspec
PS3 Not met Available functional evidence does not support a damaging effect. TP53 functional data classify p.Pro309Ser as functional in Kato transactivation testing and as no loss of function in Giacomelli data, so PS3 is not met.
vcep_functional_worksheet vcep_flowchart_for_application_of_functional_rule_codes PMID:12826609 PMID:30224644
PM4 N/A This criterion is not applicable in the TP53 VCEP specification.
cspec
BS2 Not assessed No single-source dataset of unrelated females aged 60 years or older without cancer carrying this variant was identified, so BS2 could not be assessed.
cspec
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