Classification rationale

PS3PM2PP3PP5 Likely Pathogenic

TP53 c.761T>C

The TP53 c.761T>C (p.Ile254Thr) variant has been observed in somatic cancers 9 times in COSMIC and has been reported in ClinVar, including a pathogenic expert panel assertion.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the TP53 PM2 threshold of less than 0.00003.² In TP53 functional studies curated by the TP53 VCEP, this variant was non-functional in the Kato assay and showed loss of function in additional eligible assays, supporting PS3.³ TP53-specific computational assessment supports a damaging missense effect, with a VCEP worksheet assignment of PP3_moderate, BayesDel 0.598199, REVEL 0.954, and no predicted splice impact by SpliceAI (max delta score 0.00).⁴

PS3 + PM2 + PP3 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

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_bp7bayesdelrevelspliceai ↗

Gene diagram · NM_000546.5 · variants mapped to exon structure

TP53 NM_000546.5

Fetching transcript structure from UCSC…

Applied criteria · 4 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

Not observed in any ancestry group.

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 Pathogenic (3 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.954. BayesDel score = 0.598199.

SpliceAI ↗

Functional Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.

OncoKB ↗

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; COSV52767322, n = 9 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

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

PMID PMID:12826609 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

PMID PMID:29979965

PMID PMID:29979965 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

PMID PMID:30224644

PMID PMID:30224644 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots