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

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_000546.5 · variants mapped to exon structure

TP53 NM_000546.5

Fetching transcript structure from UCSC…

Applied criteria · 4 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 · 4

Strength Supporting Moderate Strong Very strong

PS3 strong review Pathogenic

The TP53 VCEP functional worksheet assigns p.Leu344Pro to PS3 based on non-functional activity in the Kato framework, loss-of-function results across other eligible assays, and monomeric behavior in the oligomerization domain. Published functional studies for this variant support a damaging loss-of-function effect.

Functional worksheet row: L344P | Non-functional | LOF | Monomer | PS3TP53 VCEP functional flowchart

PMID:12826609 ↗PMID:9704930 ↗PMID:19106109 ↗

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614076 alleles; AF 6.1955e-07). The highest observed ancestry-specific frequency is 1/91074 in South Asian individuals (AF 1.0980e-05), which is below the TP53 VCEP PM2 threshold of 0.00003 overall and below the 0.00004 ancestry threshold used when multiple alleles are present; PM2_Supporting is met.

gnomAD v2.1 absentgnomAD v4.1 total AF 6.1955e-07best subpopulation AF 1.0980e-05

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PP3 moderate review Pathogenic

The TP53 VCEP PP3/BP4 worksheet assigns c.1031T>C as PP3_moderate with aGVGD Class C65 and BayesDel 0.485604. Additional computational evidence is concordant, including a REVEL score of 0.862, supporting a damaging missense effect.

PP3-BP4 worksheet row: c.1031T>C | p.Leu344Pro | Class C65 | 0.485604 | PP3_moderateREVEL 0.862BayesDel 0.485604

cspec ↗

PP5 supporting review Pathogenic

Expert panel ClinGen TP53 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.

TP53 VCEP marks PP5 not applicableClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PS1 No independently verified evidence was identified showing a different nucleotide change that produces the same p.Leu344Pro amino acid substitution and has already been classified under the TP53 VCEP framework, so PS1 was not applied.

PS2 No confirmed de novo occurrence with sufficient clinical and parental testing detail was identified, so PS2 was not applied.

PS4 No verified TP53 VCEP point total from affected probands was identified for this variant, so PS4 was not applied.

PM1 This missense change is not one of the TP53 codons automatically eligible for PM1 under the VCEP specification, and a verified Cancer Hotspots count for the exact p.Leu344Pro substitution was not established from the retrieved evidence.

PM5 A different missense change at codon 344 is present in ClinVar, but the retrieved evidence does not verify a qualifying TP53 VCEP pathogenic or clinically qualifying likely pathogenic comparison needed for PM5 application.

PP1 No segregation data were identified showing this variant co-segregates with Li-Fraumeni syndrome-associated cancers across informative meioses, so PP1 was not applied.

PP4 No case-level blood variant allele fraction or mosaicism data were identified to support TP53 VCEP PP4, so this criterion was not applied.

Benign

BA1 The observed population frequency does not reach the TP53 VCEP BA1 threshold of at least 0.001 in a qualifying ancestry group.

BS1 The observed population frequency is below the TP53 VCEP BS1 threshold of at least 0.0003 in a qualifying ancestry group.

BS2 No evidence was identified showing this variant in the number of unrelated cancer-free older females required for TP53 VCEP BS2, so this criterion was not applied.

BS3 Available functional evidence does not show normal or near-normal TP53 function.

BS4 No lack-of-segregation data were identified in affected family members with Li-Fraumeni syndrome-associated cancers, so BS4 was not applied.

BP4 Computational evidence does not support a benign effect.

N/A · 11 PVS1 · PM3 · PM4 · PM6 · PP2 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7

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.

Understanding the function-structure and function-mutation relationships of p53

PMID 12826609 ↗

Found