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RB1
Final classification
Likely Pathogenic
RB1 c.345_351del · p.Phe115LeufsTer8
RB1

NM_000321.2:c.345_351del is a frameshift deletion in exon 3 of RB1 predicted to produce a premature stop codon (p.Phe115LeufsTer8) and trigger nonsense-mediated decay, meeting PVS1 at very strong strength.

Gene
RB1
Transcript
NM_000321.2
HGVS · transcript:coding
NM_000321.2:c.345_351del
Consequence
N/A
GRCh38
chr13:48342676 GTTCACTT>G
GRCh37
chr13:48916812 GTTCACTT>G
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.345_351del

NM_000321.2:c.345_351del is a frameshift deletion in exon 3 of RB1 predicted to produce a premature stop codon (p.Phe115LeufsTer8) and trigger nonsense-mediated decay, meeting PVS1 at very strong strength.1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (0 alleles across >1.8 million total alleles), meeting PM2 at moderate strength.2 No benign or conflicting evidence was identified. The variant is absent from ClinVar and has not been reported in any published literature with variant-specific data.3 Combined classification: PVS1 (very strong) + PM2 (moderate) → Pathogenic under generic ACMG/AMP 2015 combination rules (PMID:25741868).4

PVS1 + PM2 → Likely Pathogenic
1 pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
3 clinvar ↗
4 generic_acmg_combination_rules
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
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      —
      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 = 0.02).
      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