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RB1c.2546_2547delLikely pathogenic
Print report
Variant interpretation report

RB1 c.2546_2547del, p.(Asn849ThrfsTer5)

NM_000321.2:c.2546_2547del NP_000312.2:p.(Asn849ThrfsTer5) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About RB1

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

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.

PM2Moderate
PM2 · moderate

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with a rare pathogenic variant.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: 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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.040 maximum delta

Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 3 not met · 13 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, supporting rarity in the general population.

Met · 2

PVS1 Very strongNM_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. Details ▾Hide ▴
Evidence considered
  • Frameshift variant in exon 25/27 producing p.Asn849ThrfsTer5
  • PTC positioned >50 nt upstream of last exon-exon junction
  • NMD predicted
  • RB1 loss of function is the established germline disease mechanism for retinoblastoma
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 ModerateThis variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with a rare pathogenic variant. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (exomes/genomes)
  • Absent from gnomAD-Canada v1.0 (genomes)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 3 · evaluated, threshold not reached

PM1 The variant does not lie within a statistically significant mutational hotspot as assessed by Cancer Hotspots, and no domain-specific enrichment was identified. Details ▾Hide ▴
Evidence considered
  • Not located in a statistically significant hotspot
BA1 BA1 requires an allele frequency >1% in population databases. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 BS1 requires an allele frequency >0.3% in population databases. This variant is absent from all gnomAD populations. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not assessed · 13 · no assessment recorded

PS2 De novo status was not assessed; no parental testing data or de novo report for this variant was identified. Details ▾Hide ▴
Still missing
  • No de novo testing data or allele-specific parental analysis available
PS3 No variant-specific functional studies were identified. Five OncoKB-curated papers were reviewed; none mentioned NM_000321.2:c.2546_2547delAT. Well-established functional evidence supporting a damaging effect is not available for this variant. Details ▾Hide ▴
Still missing
  • No variant-specific functional assays identified
PS4 No case-control or prevalence data comparing affected individuals to controls were available for this variant. Details ▾Hide ▴
Still missing
  • No case-control or cohort prevalence data
PM6 No de novo observation with unconfirmed parentage was identified for this variant. Details ▾Hide ▴
Still missing
  • No de novo report available
PP1 No segregation data in affected family members were available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data
PP4 No patient phenotype or family history data specific to this variant were available for review. Details ▾Hide ▴
Still missing
  • No patient-specific phenotype data
PP5 This variant is absent from ClinVar; no reputable source has reported it as pathogenic. Details ▾Hide ▴
Still missing
  • Not reported in ClinVar
BS2 No data on observation in healthy adults for a disorder with full penetrance expected at early age were available. Details ▾Hide ▴
Still missing
  • No healthy-adult observation data
BS3 No variant-specific functional studies demonstrating no damaging effect were identified. Five OncoKB-curated papers were reviewed; none mentioned NM_000321.2:c.2546_2547delAT. Details ▾Hide ▴
Still missing
  • No variant-specific benign functional data
BS4 No non-segregation data in affected families were available for this variant. Details ▾Hide ▴
Still missing
  • No family non-segregation data
BP5 No alternate locus observation suggesting a different molecular basis for disease was identified. Details ▾Hide ▴
Still missing
  • No alternate molecular basis identified in case
BP6 This variant is absent from ClinVar; no reputable source has classified it as benign. Details ▾Hide ▴
Still missing
  • Not reported in ClinVar
PS5 This variant is absent from ClinVar; no reputable source has classified it as pathogenic. Details ▾Hide ▴
Still missing
  • Not present in ClinVar
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to missense variants where the same amino acid change is known to be pathogenic. This variant is a frameshift deletion; PS1 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped by examiner directive. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions and stop-loss variants. This variant is a frameshift deletion, which is assessed under PVS1, not PM4. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a different missense change at the same residue known to be pathogenic. This variant is a frameshift deletion; no single-residue missense comparator can be defined. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APP3 evaluates computational evidence of deleterious effect for missense or splice-site variants. This is a frameshift deletion whose damaging mechanism (protein truncation via NMD) is captured by PVS1. SpliceAI predicts no splicing impact (max delta 0.04), and REVEL/BayesDel are not applicable to non-SNV variants. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.04 (no splicing impact)
Sources
spliceai ↗
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism. This variant is itself a truncating (frameshift) variant. Details ▾Hide ▴

No further detail was recorded.

BP2 N/ABP2 applies to variants observed in trans with a pathogenic variant in a recessive disorder. RB1-associated retinoblastoma follows autosomal dominant inheritance with high penetrance; BP2 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions without a known function. This variant is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 applies to missense or splice variants where multiple lines of computational evidence suggest no impact. This is a frameshift deletion whose damaging mechanism is protein truncation via NMD, not missense substitution or altered splicing. SpliceAI predicts no splicing impact (max delta 0.04), but this is not the relevant pathogenic mechanism for a frameshift variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.04
  • not the relevant mechanism for frameshift pathogenicity
Sources
spliceai ↗
BP7 N/ABP7 applies to silent (synonymous) variants with no predicted splicing impact. This variant is a frameshift deletion, not a synonymous substitution. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
RB1
Transcript
NM_000321.2
Coding (HGVS c.)
NM_000321.2:c.2546_2547del
Protein (HGVS p.)
NP_000312.2:p.(Asn849ThrfsTer5)
GRCh38
chr13:48476725 AAT>A
GRCh37
chr13:49050861 AAT>A

Gene diagram

Every interpreted variant in RB1, mapped onto the exon structure of NM_000321.2. Select a row to find it on the plot.

RB1NM_000321.2
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -24 bp
0.010
SpliceAI acceptor gainat +20 bp
0.040
SpliceAI donor lossat +118 bp
0.000
SpliceAI donor gainat -269 bp
0.000
Pangolin splice lossmagnitude shown
-0.150
Pangolin splice gain
0.090

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/APP3 evaluates computational evidence of deleterious effect for missense or splice-site variants. This is a frameshift deletion whose damaging mechanism (protein truncation via NMD) is captured by PVS1. SpliceAI predicts no splicing impact (max delta 0.04), and REVEL/BayesDel are not applicable to non-SNV variants. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.04 (no splicing impact)
Sources
spliceai ↗
BP4 N/ABP4 applies to missense or splice variants where multiple lines of computational evidence suggest no impact. This is a frameshift deletion whose damaging mechanism is protein truncation via NMD, not missense substitution or altered splicing. SpliceAI predicts no splicing impact (max delta 0.04), but this is not the relevant pathogenic mechanism for a frameshift variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.04
  • not the relevant mechanism for frameshift pathogenicity
Sources
spliceai ↗
BP7 N/ABP7 applies to silent (synonymous) variants with no predicted splicing impact. This variant is a frameshift deletion, not a synonymous substitution. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Rapid identification of germline mutations in retinoblastoma by protein truncation testing.
    Describes protein truncation testing (PTT) for rapid detection of germline RB1 mutations in 27 hereditary retinoblastoma kindreds. NM_000321.2:c.2546_2547delAT was not identified in this paper.
    Does not name this variant
    PMID 14769601 ↗
  • RB1 mutations and second primary malignancies after hereditary retinoblastoma.
    Retrospective cohort study of 199 hereditary retinoblastoma survivors examining RB1 germline mutations and second primary malignancy risk. The study discusses RB1 mutations categorically (frameshift, nonsense, etc.) but NM_000321.2:c.2546_2547delAT was not identified in this paper.
    Does not name this variant
    PMID 22205104 ↗
  • Deletion of Rb1 induces both hyperproliferation and cell death in murine germinal center B cells.
    Murine study examining functional consequences of conditional Rb1 deletion in germinal center B cells. Uses a floxed Rb1 mouse model; no human variant NM_000321.2:c.2546_2547delAT is reported.
    Does not name this variant
    PMID 26607597 ↗
  • The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial.
    Circulating tumor DNA analysis of the PALOMA-3 trial examining resistance to palbociclib plus fulvestrant in breast cancer. RB1 mutations were detected in ctDNA as acquired resistance mechanisms, but NM_000321.2:c.2546_2547delAT was not identified among the reported mutations.
    Does not name this variant
    PMID 30206110 ↗
  • RB1 Deletion in Retinoblastoma Protein Pathway-Disrupted Cells Results in DNA Damage and Cancer Progression.
    Investigates DNA damage and cancer progression following RB1 deletion in cells with pre-existing RB pathway disruption. NM_000321.2:c.2546_2547delAT was not identified in this paper.
    Does not name this variant
    PMID 31138663 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.040 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.