0%
RB1c.345_351delLikely pathogenic
Print report
Variant interpretation report

RB1 c.345_351del, p.(Phe115LeufsTer8)

NM_000321.2:c.345_351del NP_000312.2:p.(Phe115LeufsTer8) 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.345_351del is a 7bp frameshift deletion in exon 3 of RB1, predicted to produce a premature stop codon at position 122 (p.Phe115LeufsTer8), triggering nonsense-mediated decay. RB1 loss-of-function is a well-established disease mechanism for retinoblastoma, and this null variant meets PVS1 at full (very strong) strength under the generic ClinGen SVI PVS1 framework (PMC6185798).

PM2Moderate
PM2 · moderate

NM_000321.2:c.345_351del is absent from all population databases: gnomAD v2.1 (0/~251,496 alleles), gnomAD v4.1 (0/~1,614,324 alleles), and gnomAD-Canada v1.0 (0 observed). This complete absence in large, diverse control populations meets PM2 at moderate strength under generic ACMG/AMP rules.

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
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. 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.

28 criteria with recorded statuses: 2 met · 16 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

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.

Combined classification: PVS1 (very strong) + PM2 (moderate) → Pathogenic under generic ACMG/AMP 2015 combination rules (PMID:25741868).

Met · 2

PVS1 Very strongNM_000321.2:c.345_351del is a 7bp frameshift deletion in exon 3 of RB1, predicted to produce a premature stop codon at position 122 (p.Phe115LeufsTer8), triggering nonsense-mediated decay. RB1 loss-of-function is a well-established disease mechanism for retinoblastoma, and this null variant meets PVS1 at full (very strong) strength under the generic ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Frameshift deletion c.345_351del introduces premature termination at codon 122 in exon 3 of 27
  • well upstream of the last exon and predicted to undergo NMD
  • RB1 germline loss-of-function is a confirmed disease mechanism for retinoblastoma
  • supported by published literature
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 ModerateNM_000321.2:c.345_351del is absent from all population databases: gnomAD v2.1 (0/~251,496 alleles), gnomAD v4.1 (0/~1,614,324 alleles), and gnomAD-Canada v1.0 (0 observed). This complete absence in large, diverse control populations meets PM2 at moderate strength under generic ACMG/AMP rules. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes
  • n~125
  • 748)
  • Absent from gnomAD v4.1 (exomes
  • n~807
  • 162)
  • Absent from gnomAD-Canada v1.0 (genomes)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 16 · evaluated, threshold not reached

PS2 No de novo data are available for this variant. Neither ClinVar submissions nor published literature provide de novo confirmation. Details ▾Hide ▴
Still missing
  • No parental testing or de novo confirmation available
PS3 No well-established functional studies of NM_000321.2:c.345_351del were identified. OncoKB classifies this variant as 'Likely Oncogenic' based on somatic/oncogenicity curation, which does not constitute independent germline functional evidence for PS3. Details ▾Hide ▴
Evidence considered
  • OncoKB assigns Likely Oncogenic classification with Likely Loss-of-function biological effect
  • but this is a somatic oncogenicity label
  • not a validated germline functional assay
Still missing
  • No variant-specific functional studies (e.g.
  • in vitro expression
  • protein function assays) identified
Sources
oncokb ↗
PS4 No case-control or prevalence data are available. The variant is absent from ClinVar and has not been reported in affected individuals through published studies or databases. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no affected vs. control prevalence statistics available
Still missing
  • No case counts or case-control data available
Sources
clinvar ↗
PM1 The variant c.345_351del lies in exon 3 (N-terminal region, codon 115), outside the well-characterized RB1 pocket domain (codons ~380–785). No statistically significant hotspot encompasses this position, and the Cancer Hotspots database does not list this variant or residue as a significant hotspot. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots database: residue not significant
  • exact variant not listed
  • Variant lies in N-terminal region (codon 115)
  • not within the RB1 pocket domain critical functional region
PM6 No de novo data are available for this variant. PM6 requires a confirmed de novo observation with maternity and paternity confirmation. Details ▾Hide ▴
Still missing
  • No de novo testing available
PP1 No segregation data are available for this variant. No family studies or cosegregation analyses have been reported in ClinVar or published literature. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 No patient phenotype or family history data are provided in the case. PP4 requires that the patient's phenotype is highly specific for a disease with a single genetic etiology and that this has been confirmed in the case. Details ▾Hide ▴
Still missing
  • No patient phenotype or clinical history provided
PP5 No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar, and OncoKB's 'Likely Oncogenic' classification is a somatic oncogenicity label, not an ACMG/AMP germline assertion. Details ▾Hide ▴
Evidence considered
  • ClinVar: variant absent (no submissions
  • no classification)
  • OncoKB: Likely Oncogenic classification is somatic/oncogenicity-focused
  • not a germline ACMG pathogenicity assertion
Sources
clinvar ↗oncokb ↗
BA1 BA1 requires an allele frequency >1% in population databases. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: absent
  • gnomAD-Canada: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 BS1 requires an allele frequency greater than expected for the disorder (>0.3% per the adopted threshold). The variant is absent from all population databases. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent (0/251
  • 496 alleles)
  • gnomAD v4.1: absent (0/1
  • 614
  • 324 alleles)
  • gnomAD-Canada: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 BS2 requires observation in healthy adults with full penetrance expected, or observation in trans with a pathogenic variant. The variant is absent from population databases; no observation in healthy individuals is available. Details ▾Hide ▴
Still missing
  • Not observed in any healthy controls
BS3 No well-established functional studies demonstrate a benign or neutral effect for this variant. No functional evidence suggesting normal protein function was identified. Details ▾Hide ▴
Still missing
  • No functional studies demonstrating neutral/benign effect
BS4 No segregation data are available to demonstrate lack of segregation with disease. No family studies have been reported for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 BP2 requires observation in trans with a dominant pathogenic variant or in cis with a pathogenic variant in any inheritance pattern. No such data are available for this variant. Details ▾Hide ▴
Still missing
  • No trans/cis phase data available
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such clinical context is available for this variant. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data available
BP6 BP6 requires a reputable source to report the variant as benign. The variant is absent from ClinVar and no source classifies it as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: variant absent — no benign classification available
Sources
clinvar ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to a nucleotide change producing the same amino acid change as an established pathogenic missense variant. This is a 7bp frameshift deletion — no same-amino-acid comparator concept applies. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants causing protein length changes. This is an out-of-frame frameshift deletion producing a premature termination codon, assessed under PVS1. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a novel missense change at a residue where a different pathogenic missense change has been established. This is a frameshift deletion, not a missense variant; classic same-residue PM5 semantics cannot be applied. Details ▾Hide ▴
Evidence considered
  • pm5_candidates.json: eligible_for_classic_pm5_search = false
  • no same-residue comparator variants identified
Sources
pm5_candidates
PP2 N/APP2 assesses the rate of benign missense variation in the gene. This is a frameshift deletion, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APP3 evaluates multiple lines of computational evidence for deleterious effect. For a frameshift null variant predicted to undergo NMD, the deleterious effect is inherent to the variant type and already captured by PVS1. SpliceAI shows no significant splice impact (max delta score 0.02), and REVEL/BayesDel are unavailable (not a SNV). Applying PP3 alongside PVS1 for this null variant would constitute double-counting. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.02 (no significant splice alteration)
  • REVEL and BayesDel not applicable (variant is not a SNV)
  • HCI prior not available (gene not in HCI prior database)
Sources
spliceai ↗
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a frameshift truncating variant, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions or insertions in repetitive regions. This is an out-of-frame frameshift deletion, not an in-frame variant. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 evaluates computational evidence suggesting no impact on the gene product. For a frameshift null variant predicted to cause NMD and complete loss of protein function, the concept of 'no impact' is inapplicable. The SpliceAI max delta score of 0.02 addresses splicing only and does not override the established null effect of the frameshift. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.02 (no significant splice alteration)
  • REVEL and BayesDel not applicable (variant is not a SNV)
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 requires a reputable source to have recently reported the variant as pathogenic with evidence unavailable for independent evaluation. No ClinVar entry or other reputable source classifies this variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
RB1
Transcript
NM_000321.2
Coding (HGVS c.)
NM_000321.2:c.345_351del
Protein (HGVS p.)
NP_000312.2:p.(Phe115LeufsTer8)
GRCh38
chr13:48342676 GTTCACTT>G
GRCh37
chr13:48916812 GTTCACTT>G

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 -22 bp
0.020
SpliceAI acceptor gainat -73 bp
0.020
SpliceAI donor lossat +38 bp
0.000
SpliceAI donor gainat +285 bp
0.000
Pangolin splice lossmagnitude shown
-0.100
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/APP3 evaluates multiple lines of computational evidence for deleterious effect. For a frameshift null variant predicted to undergo NMD, the deleterious effect is inherent to the variant type and already captured by PVS1. SpliceAI shows no significant splice impact (max delta score 0.02), and REVEL/BayesDel are unavailable (not a SNV). Applying PP3 alongside PVS1 for this null variant would constitute double-counting. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.02 (no significant splice alteration)
  • REVEL and BayesDel not applicable (variant is not a SNV)
  • HCI prior not available (gene not in HCI prior database)
Sources
spliceai ↗
BP4 N/ABP4 evaluates computational evidence suggesting no impact on the gene product. For a frameshift null variant predicted to cause NMD and complete loss of protein function, the concept of 'no impact' is inapplicable. The SpliceAI max delta score of 0.02 addresses splicing only and does not override the established null effect of the frameshift. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.02 (no significant splice alteration)
  • REVEL and BayesDel not applicable (variant is not a SNV)
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

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 probands with hereditary retinoblastoma. NM_000321.2:c.345_351del was not identified in the abstract or the available screenshot; no variant-level data were extractable.
    Does not name this variant
    PMID 14769601 ↗
  • RB1 mutations and second primary malignancies after hereditary retinoblastoma.
    Retrospective cohort study of 199 survivors of hereditary retinoblastoma investigating the association between specific RB1 germline mutations and second primary malignancy risk. NM_000321.2:c.345_351del was not listed among the RB1 mutations analyzed in this cohort.
    Does not name this variant
    PMID 22205104 ↗
  • Deletion of Rb1 induces both hyperproliferation and cell death in murine germinal center B cells.
    Mouse model study examining the functional consequences of conditional Rb1 deletion in germinal center B cells, focused on multiple myeloma pathogenesis. NM_000321.2:c.345_351del is a human RB1 variant not relevant to the murine conditional knockout model used.
    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.
    Reports circulating tumor DNA sequencing from the PALOMA-3 phase III trial of palbociclib plus fulvestrant in advanced breast cancer, identifying acquired RB1 mutations as a resistance mechanism. NM_000321.2:c.345_351del was not among the RB1 mutations reported in this study.
    Does not name this variant
    PMID 30206110 ↗
  • RB1 Deletion in Retinoblastoma Protein Pathway-Disrupted Cells Results in DNA Damage and Cancer Progression.
    Investigates the consequences of RB1 deletion in cells with pre-existing RB pathway disruption, demonstrating increased DNA damage and cancer progression. NM_000321.2:c.345_351del was not among the specific RB1 mutations studied; the work uses engineered Rb1 deletion models.
    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 0.020 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 = 0.02).

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.