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RB1
Final classification
Likely Pathogenic
RB1 c.2546_2547del · p.Asn849ThrfsTer5
RB1

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.

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 applied · 15 assessed
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PVS1 very strong Pathogenic
NM_000321.2:c.2546_2547delAT is a frameshift deletion in exon 25 of 27, introducing a premature termination codon (p.Asn849ThrfsTer5) predicted to undergo nonsense-mediated decay (>50 bp upstream of the last exon-exon junction). RB1 is a well-established tumor suppressor gene where loss of function is the known disease mechanism for retinoblastoma. Under ClinGen SVI PVS1 recommendations (PMC6185798), this null variant in a gene where LoF is a known mechanism merits PVS1 at full (very strong) weight.
Frameshift variant in exon 25/27 producing p.Asn849ThrfsTer5PTC positioned >50 nt upstream of last exon-exon junctionNMD predicted
pvs1_generic_framework ↗
✓
PM2 moderate Pathogenic
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with a rare pathogenic variant.
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes/genomes)Absent from gnomAD-Canada v1.0 (genomes)
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied
Pathogenic
PS2 De novo status was not assessed; no parental testing data or de novo report for this variant was identified.
PS3 No variant-specific functional studies were identified.
PS4 No case-control or prevalence data comparing affected individuals to controls were available for this variant.
PM1 The variant does not lie within a statistically significant mutational hotspot as assessed by Cancer Hotspots, and no domain-specific enrichment was identified.
PM6 No de novo observation with unconfirmed parentage was identified for this variant.
PP1 No segregation data in affected family members were available for this variant.
PP4 No patient phenotype or family history data specific to this variant were available for review.
PP5 This variant is absent from ClinVar; no reputable source has reported it as pathogenic.
Benign
BA1 BA1 requires an allele frequency >1% in population databases.
BS1 BS1 requires an allele frequency >0.3% in population databases.
BS2 No data on observation in healthy adults for a disorder with full penetrance expected at early age were available.
BS3 No variant-specific functional studies demonstrating no damaging effect were identified.
BS4 No non-segregation data in affected families were available for this variant.
BP5 No alternate locus observation suggesting a different molecular basis for disease was identified.
BP6 This variant is absent from ClinVar; no reputable source has classified it as benign.
N/A · 11 PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP2 · BP3 · BP4 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
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 screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
SpliceAI ↗
Functional / OncoKB screenshot
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 screenshot
COSMIC
Cancer hotspots screenshot
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