Classification rationale

PVS1PM2 Likely Pathogenic

TP53 c.832_839dup

The TP53 c.832_839dup (p.Arg280SerfsTer68) variant has not been observed in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, supporting rarity below the TP53 VCEP PM2 threshold.² The duplication causes a frameshift predicted to truncate TP53 at p.Arg280SerfsTer68, and because the premature stop is upstream of p.Lys351, the TP53 VCEP PVS1 flowchart supports PVS1.³ SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.⁴

PVS1 + PM2 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

3 cspec ↗vcep_pvs1_flowchartpvs1_gene_contextpvs1_variant_assessment

4 spliceai ↗

Gene diagram · NM_000546.6 · variants mapped to exon structure

TP53 NM_000546.6

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 8 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

This variant is a frameshift duplication in TP53 predicted to produce p.(Arg280SerfsTer68). Under the TP53 VCEP PVS1 flowchart, frameshift variants with a premature termination codon upstream of p.Lys351 are expected to undergo nonsense-mediated decay and meet PVS1.

Protein consequence is p.(Arg280SerfsTer68).The affected residue is upstream of p.Lys351 in the TP53 PVS1 flowchart.TP53 loss of function is an established disease mechanism in the VCEP framework.

cspec ↗

✓

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall and below 0.00004 within any non-founder ancestry group.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.Absent from gnomAD-Canada v1.0.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS2 No confirmed de novo observations or point-based PS2 evidence were identified for this variant.

PS4 No proband-based Li-Fraumeni syndrome point data were identified to determine whether the TP53 VCEP PS4 thresholds are met.

PP1 No segregation data were identified to assess cosegregation with Li-Fraumeni syndrome-associated cancers.

PP4 No phenotype-specific TP53 VCEP PP4 evidence was identified, including no low-variant-allele-fraction observation data needed for this rule.

Benign

BA1 This variant is absent from population databases and does not reach the TP53 VCEP BA1 stand-alone benign threshold of at least 0.001.

BS1 This variant is absent from population databases and does not reach the TP53 VCEP BS1 benign threshold of at least 0.0003 in a qualifying ancestry group.

BS2 No data were identified showing this variant in unrelated females aged at least 60 years without cancer from a single source, so BS2 cannot be assessed.

BS4 No family data were identified showing lack of segregation with Li-Fraumeni syndrome-associated cancers, so BS4 cannot be assessed.

N/A · 18 PS1 · PS3 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP3 · PP5 · BS3 · BP1 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7

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.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

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 Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely 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 not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

11753428 ↗ A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. ONCOKB

11900253 ↗ Rescuing the function of mutant p53. ONCOKB

16007150 ↗ The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library. ONCOKB

19336573 ↗ High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. ONCOKB

21467160 ↗ Prognostic significance of truncating TP53 mutations in head and neck squamous cell carcinoma. ONCOKB

27759562 ↗ TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions. ONCOKB

Re-run this variant?