Classification rationale

PS3PM2PP3PP5 Likely Pathogenic

TP53 c.1031T>C

The TP53 c.1031T>C (p.Leu344Pro; p.L344P) variant has been observed in somatic cancer curation resources and has been reported in ClinVar, including a ClinGen TP53 Variant Curation Expert Panel likely pathogenic assertion.¹ This variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (1/1614076 alleles; AF 6.1955e-07), with the highest observed population frequency in South Asian individuals of 1/91074 (AF 1.0980e-05), supporting rarity for TP53.² In TP53 functional studies summarized by the TP53 VCEP, p.Leu344Pro showed non-functional activity, loss-of-function behavior across eligible assays, and monomeric oligomerization-domain behavior, supporting a damaging loss-of-function effect.³ Computational evidence is concordant with a damaging missense effect, with a TP53 VCEP pre-assigned PP3_moderate call, BayesDel 0.485604, and REVEL 0.862.⁴

PS3 + PM2 + PP3 + PP5 → Likely Pathogenic

1 oncokb ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:9704930 ↗PMID:19106109 ↗PMID:19454241 ↗PMID:20978130 ↗

4 vcep_pp3_bp4_codesbayesdelrevel

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

This variant is present in gnomAD v4.1 (AF= 6.1955e-07; MAF= 0.00006%, 1/1614076 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09801e-05; MAF= 0.00110%, 1/91074 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 / 1,614,076
0 hom

South Asian

1 / 91,074

0.0011%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, 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 Pathogenic (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Likely 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 = 0.862. BayesDel score = 0.485604.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely 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; COSV52687285, n = 11 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

5papers 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