Analysis in progress

Initialising…

complete

This report is still being assembled — sections appear as each stage finishes. It isn't final yet.

RB1

Final classification

Likely Pathogenic

RB1 c.2546_2547del · p.Asn849ThrfsTer5

RB1

Gene

RB1

Transcript

NM_000321.2

HGVS · transcript:coding

NM_000321.2:c.2546_2547del

Consequence

N/A

GRCh38

chr13:48476725 AAT>A

GRCh37

chr13:49050861 AAT>A

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.

Classification rationale

PVS1PM2 Likely Pathogenic

RB1 c.2546_2547del

NM_000321.2:c.2546_2547delAT is a frameshift deletion in exon 25 of RB1, introducing a premature termination codon (p.Asn849ThrfsTer5) predicted to undergo nonsense-mediated decay. RB1 loss of function is the established germline disease mechanism for retinoblastoma.¹ This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, supporting rarity in the general population.²

PVS1 + PM2 → Likely Pathogenic

1 pvs1_generic_framework ↗pvs1_gene_context

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Gene diagram · NM_000321.2 · variants mapped to exon structure

RB1 NM_000321.2

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 = 0.04).

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 does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

14769601 ↗ Rapid identification of germline mutations in retinoblastoma by protein truncation testing. ONCOKB

22205104 ↗ RB1 mutations and second primary malignancies after hereditary retinoblastoma. ONCOKB

26607597 ↗ Deletion of Rb1 induces both hyperproliferation and cell death in murine germinal center B cells. ONCOKB

30206110 ↗ The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial. ONCOKB

31138663 ↗ RB1 Deletion in Retinoblastoma Protein Pathway-Disrupted Cells Results in DNA Damage and Cancer Progression. ONCOKB

Re-run this variant?