Classification rationale

PVS1PM2 Likely Pathogenic

RB1 c.2439dup nonsense · exon 23

PVS1 very strong: RB1 c.2439dup creates p.Lys814Ter and is predicted to undergo nonsense-mediated decay. PM2 supporting: c.2439dupT is absent from gnomAD v2.1 and v4.1.

PVS1 + PM2 → Likely Pathogenic

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

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 · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

Met, very strong: RB1 c.2439dup creates p.Lys814Ter in exon 23 of 27, predicting NMD and loss of 116 of 929 amino acids.

VariantValidator maps NM_000321.2:c.2439dup to RB1 coding exon 23 and confirms NP_000312.2:p.(K814*); the selected RefSeq transcript is NM_000321.2.Mutalyzer predicts a premature stop at p.(Lys814Ter), with the predicted protein ending at residue 813 versus the 929-residue reference protein, a loss of 116 amino acids.The gene-level PVS1 eligibility assessment supports RB1 germline loss of function as a disease mechanism and identifies no RB1-specific CSPEC/VCEP specification, so the generic ClinGen SVI framework applies.

pvs1_generic_framework ↗PMID:22205104 ↗

PM2 supporting Pathogenic

Met at supporting strength: variant absent from gnomAD v2.1 and v4.1, with observed allele frequency 0 versus the <=0.0001 PM2 threshold.

gnomAD v2.1 reports the variant as absent, with no observed allele count or frequency.gnomAD v4.1 reports the variant as absent, with no observed allele count or frequency.The supplied generic PM2 threshold is allele frequency <=0.0001 at supporting strength under the ClinGen SVI recommendation (PMID:25741868).

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no parental genotypes or confirmed maternity and paternity establish de novo occurrence of NM_000321.2:c.2439dupT.

PS3 Not assessed: no validated functional assay tested RB1 c.2439dup or p.Lys814Ter, so variant-specific damaging evidence is unavailable.

PS4 Not assessed: no variant-specific case-control counts or enrichment statistic were available to evaluate PS4.

PM6 Not assessed: no proband-level report documents apparently de novo NM_000321.2:c.2439dupT without parental testing.

PP1 Not assessed: zero informative meioses or affected relatives are documented for segregation of NM_000321.2:c.2439dupT.

PP4 Not assessed: no individual clinical phenotype was available to determine whether it is highly specific for an RB1-related disorder.

PP5 Not met: ClinVar has no exact-variant expert-panel Pathogenic/Likely pathogenic classification for c.2439dupT.

Benign

BA1 Not met: variant absent from gnomAD v2.1 and v4.1, with observed allele frequency 0 versus the >=0.05 BA1 threshold.

BS1 Not met: variant absent from gnomAD v2.1 and v4.1, with observed allele frequency 0 versus the >=0.01 BS1 threshold.

BS2 Not assessed: no documented unaffected carriers or homozygotes are available to evaluate the BS2 requirement.

BS3 Not assessed: no validated benign functional assay tested RB1 c.2439dup or p.Lys814Ter with appropriate controls.

BS4 Not assessed: no tested unaffected relatives or informative non-segregation observations are documented for NM_000321.2:c.2439dupT.

BP2 Not assessed: no second pathogenic variant or documented cis/trans phase is available for this RB1 variant.

BP5 Not assessed: no alternate pathogenic variant or established alternative molecular explanation was documented for the phenotype.

BP6 Not met: ClinVar has no exact-variant expert-panel Benign/Likely benign classification for c.2439dupT.

N/A · 11 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7

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

Not available in 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 = 0.03).

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 ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 4 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

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

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 4 PMIDs not cited in assessment

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

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