Starting

Initialising…

TP53

Final classification

Likely Pathogenic

TP53 c.832_839dup · p.Arg280SerfsTer68

TP53

The TP53 c.832_839dup (p.Arg280SerfsTer68) variant has not been observed in COSMIC and has not been reported in ClinVar.

Gene

TP53

Transcript

NM_000546.6

HGVS · transcript:coding

NM_000546.6:c.832_839dup

Consequence

N/A

GRCh38

chr17:7673780 T>TCTCCCAGG

GRCh37

chr17:7577098 T>TCTCCCAGG

Basis Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PVS1 very strong (+8) + PM2 supporting (+1) = 9 points, which maps to Likely Pathogenic. ▾

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PVS1 very strong (+8) + PM2 supporting (+1) = 9 points, which maps to Likely Pathogenic.

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 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

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.

🇨🇦 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