Classification rationale

PM2 BS3BP4 Unclassified

TP53 c.925C>T · exon NC_000017.10

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.¹ 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 0.00003.² 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 BS3.³ 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.⁴

PM2 + BS3 + BP4 → Unclassified

1 clinvar ↗hotspots ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609PMID:30224644

4 spliceai ↗bayesdelrevelvcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19531e-07; MAF= 0.00006%, 1/1614124 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59969e-05; MAF= 0.00160%, 1/62512 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,614,124
0 hom

Remaining individuals

1 / 62,512

0.0016%

+ 9 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 458575)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV52729434, n = 5 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 9 further PMIDs triaged but not cited — see Sources & References.

PMID PMID:12826609

PMID PMID:12826609 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BS3 supports · met

PMID PMID:30224644

PMID PMID:30224644 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BS3 supports · met

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 9 PMIDs not cited in assessment

12826609 ↗ Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

29300620 ↗ TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children. CLINVAR

29979965 ↗ A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. CLINVAR

30224644 ↗ Mutational processes shape the landscape of TP53 mutations in human cancer. CLINVAR

34793697 ↗ Closing the gap: Systematic integration of multiplexed functional data resolves variants of uncertain significance in BRCA1, TP53, and PTEN. CLINVAR

38645101 ↗ Defining and Reducing Variant Classification Disparities. CLINVAR

12692171 ↗ American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR