0%
complete
Final classification
VUS
PM2
RB1
c.275_282del
p.Ile92LysfsTer15
frameshift · exon 3
Gene context NCBI Gene ↗ OncoKB ↗

RB1 encodes a protein that acts as a key brake on cell division: in its active form it blocks cells from moving from the G1 into the S phase of the cell cycle, and it also helps maintain the structure of packaged DNA in the nucleus. It was the first tumor suppressor gene identified. Loss of RB1 function removes this brake, leading to uncontrolled cell growth and contributing to many cancers, including retinoblastoma (a childhood eye cancer), bladder cancer, osteogenic sarcoma, and cancers of the lung, breast, and prostate. Inherited changes in RB1 predispose children to retinoblastoma and adults to sarcomas and other tumors.

This variant

Uncertain Significance: PM2 (supporting) is met because the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets.

Transcript
NM_000321.2
HGVS · transcript:coding
NM_000321.2:c.275_282del
GRCh38
chr13:48342608 ATTCAAAAG>A
GRCh37
chr13:48916744 ATTCAAAAG>A
Uncertain Significance: only PM2 (supporting) is met under the generic ACMG fallback; PVS1 could not be assessed due to an agent processing failure.
Classification rationale
PM2 VUS
RB1 c.275_282del frameshift · exon 3

Uncertain Significance: PM2 (supporting) is met because the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets.

PM2 → VUS
Gene diagram · NM_000321.2 · variants mapped to exon structure
RB1 NM_000321.2
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
Met (supporting): variant absent from gnomAD v2.1, v4.1, and both non-cancer subsets, meeting PM2 absent/extremely-rare criteria.
gnomAD v2.1 exome direct URL lookup (13-48916744-ATTCAAAAG-A) returned search_status=absent, found=false, evidence_sentence='Absent from gnomAD v2.1.'gnomAD v4.1 direct URL lookup (chr13-48342608-ATTCAAAAG-A) returned search_status=absent, found=false, evidence_sentence='Absent from gnomAD v4.1.'GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER subset lookups at the same coordinates also returned absent, confirming absence irrespective of which population source (all-comers vs non-cancer) is applicable.
gnomad_v2 ↗gnomad_v4 ↗
Assessed · not applied · 3 not met · 11 not assessed
Pathogenic
PVS1 PVS1 could not be assessed because its agent did not produce valid output.
PS2 Not assessed: no proband/parental trio or de novo confirmation data present in the case evidence.
PS3 Not assessed: no functional assay data specific to this exact RB1 frameshift variant was found in retrieved literature.
PS4 Not assessed: no case-control enrichment or odds-ratio data specific to this exact variant were available.
PM6 Not assessed: no assumed-de-novo or parental data available to evaluate PM6.
PP1 Not assessed: no family segregation or meiosis data for this specific variant is available.
PP4 Not assessed: no patient-specific phenotype or family history data for this variant were provided.
Benign
BA1 Not met: variant absent from gnomAD v2.1/v4.1 (all-comers and non-cancer subsets), so allele frequency is 0, far below the BA1 threshold.
BS1 Not met: variant absent from all gnomAD releases (AF=0), well below the BS1 frequency threshold for RB1 disease prevalence.
BS2 Not met: variant absent from all gnomAD cohorts, so no homozygous or unaffected-carrier observations exist to support BS2.
BS3 Not assessed: no functional assay evidence of normal/benign protein activity exists for this frameshift variant.
BS4 Not assessed: no family segregation data available to evaluate non-segregation for BS4.
BP2 Not assessed: no proband genotype, second-variant, or trans/cis phase data are available anywhere in the case record.
BP5 Not assessed: no case data identifying an alternate molecular diagnosis for a carrier of this variant were available.
N/A · 13 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · PP5 · BP1 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
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 = 0.05).
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