RB1c.1027_1028delPathogenic

Print report

Variant interpretation report

RB1 c.1027_1028del, p.(Leu343SerfsTer3)

NM_000321.2:c.1027_1028del NP_000312.2:p.(Leu343SerfsTer3) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

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

Pathogenic.A 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.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 1 Pathogenic
Pipeline record: 31 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_000321.2:c.1027_1028del is a frameshift deletion in exon 10 of 27, predicted to introduce a premature termination codon at p.(Leu343SerfsTer3). NMD is expected as the stop codon occurs well before the last exon-exon junction. RB1 is a well-established tumor suppressor gene where loss of function is the accepted disease mechanism for retinoblastoma and associated cancers. Under ClinGen SVI PVS1 recommendations (PMC6185798), frameshift null variants in genes with established LOF mechanism are assigned PVS1 at very strong strength.
PM1 (moderate): This frameshift variant truncates the RB1 protein at p.Leu343, completely removing the pocket domain (spanning approximately residues 380-785), which is the critical functional domain responsible for E2F binding and tumor suppressor activity. The RB1 pocket domain is one of the most well-characterized functional domains in tumor biology. Although the variant is not located within a statistically significant hotspot at cancerhotspots.org, it removes a well-established critical functional domain, satisfying PM1 at moderate strength per domain-level application rules.
PM2 (supporting): This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), supporting a pathogenic role as a rare variant absent from the general population.

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: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PVS1Very strong

PVS1 · very strong

NM_000321.2:c.1027_1028del is a frameshift deletion in exon 10 of 27, predicted to introduce a premature termination codon at p.(Leu343SerfsTer3). NMD is expected as the stop codon occurs well before the last exon-exon junction. RB1 is a well-established tumor suppressor gene where loss of function is the accepted disease mechanism for retinoblastoma and associated cancers. Under ClinGen SVI PVS1 recommendations (PMC6185798), frameshift null variants in genes with established LOF mechanism are assigned PVS1 at very strong strength.

PM1Moderate

PM1 · moderate

This frameshift variant truncates the RB1 protein at p.Leu343, completely removing the pocket domain (spanning approximately residues 380-785), which is the critical functional domain responsible for E2F binding and tumor suppressor activity. The RB1 pocket domain is one of the most well-characterized functional domains in tumor biology. Although the variant is not located within a statistically significant hotspot at cancerhotspots.org, it removes a well-established critical functional domain, satisfying PM1 at moderate strength per domain-level application rules.

PM2Supporting

PM2 · supporting

This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), supporting a pathogenic role as a rare variant absent from the general population.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: 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, PM1 moderate, PM2 supporting; combination = 1 very strong + 1 moderate + 1 supporting, which maps to Pathogenic.

02The sources

Evidence at a glance

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

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.050 maximum delta

Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

1 reported laboratory submissions

1 Pathogenic. ClinVar API review status: criteria provided, single submitter.

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

COSMIC could not be reviewed because the browser session was redirected to the login page before search results were available.

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: 3 met · 10 not met · 7 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000321.2:c.1027_1028del (p.Leu343SerfsTer3) is a frameshift deletion in exon 10 of the RB1 gene, predicted to cause nonsense-mediated decay and complete loss of protein function. RB1 is a well-established tumor suppressor where loss of function is the accepted disease mechanism for retinoblastoma.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare pathogenic variant not observed in the general population.

The frameshift at codon 343 removes the entire RB1 pocket domain, a critical functional domain for E2F binding and tumor suppressor activity.

ClinVar classifies this variant as Pathogenic (Variation ID: 3236941, 1-star, single submitter). No variant-specific functional studies or clinical case reports were identified in the peer-reviewed literature.

Met · 3

PVS1 Very strongNM_000321.2:c.1027_1028del is a frameshift deletion in exon 10 of 27, predicted to introduce a premature termination codon at p.(Leu343SerfsTer3). NMD is expected as the stop codon occurs well before the last exon-exon junction. RB1 is a well-established tumor suppressor gene where loss of function is the accepted disease mechanism for retinoblastoma and associated cancers. Under ClinGen SVI PVS1 recommendations (PMC6185798), frameshift null variants in genes with established LOF mechanism are assigned PVS1 at very strong strength. Details ▾Hide ▴

Evidence considered

Frameshift variant in exon 10/27 introducing PTC at codon 345 (of 929)
NMD expected
RB1 is a well-established tumor suppressor with LOF as disease mechanism
ClinGen SVI PVS1 framework (PMC6185798) supports PVS1 at very strong for null variants in LOF genes

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

PM1 ModerateThis frameshift variant truncates the RB1 protein at p.Leu343, completely removing the pocket domain (spanning approximately residues 380-785), which is the critical functional domain responsible for E2F binding and tumor suppressor activity. The RB1 pocket domain is one of the most well-characterized functional domains in tumor biology. Although the variant is not located within a statistically significant hotspot at cancerhotspots.org, it removes a well-established critical functional domain, satisfying PM1 at moderate strength per domain-level application rules. Details ▾Hide ▴

Evidence considered

Frameshift at p.Leu343 removes the entire RB1 pocket domain (critical for E2F binding and tumor suppression)
RB1 pocket domain is a well-characterized functional domain essential for tumor suppressor activity

Sources

pvs1_gene_context

PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), supporting a pathogenic role as a rare variant absent from the general population. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (population allele frequency 0.0%)
Absent from gnomAD v4.1 (population allele frequency 0.0%)
Absent from gnomAD-Canada v1.0

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 10 · evaluated, threshold not reached

PS3 No functional studies directly testing NM_000321.2:c.1027_1028del were identified. Seven full-text publications were reviewed; none contained variant-specific functional data. OncoKB classifies this variant as Likely Oncogenic with Likely Loss-of-function based on curated literature context, but the underlying publications do not test this specific variant experimentally. Details ▾Hide ▴

Evidence considered

OncoKB classifies as Likely Oncogenic / Likely Loss-of-function (curated literature context
not direct experimental testing of this variant)
No variant-specific functional assays found in reviewed publications

Still missing

No direct functional characterization of NM_000321.2:c.1027_1028del in the literature

Sources

oncokb ↗

PS4 ClinVar submission SCV005046057 reports 2 cases (1 bilateral, 1 unilateral) from 1 pedigree, but this is a single submitter with no validated publication trail. The PMIDs cited by the ClinVar entry are all general practice guidelines (e.g., ACMG SF lists, NSGC counseling recommendations), not clinical studies reporting case-level data for this variant. No peer-reviewed publication documenting affected individuals with this variant was identified in the literature reviewed. Details ▾Hide ▴

Evidence considered

ClinVar: 1 submitter reports 2 cases from 1 pedigree
but submission is not exact-match validated and lacks published evidence

Still missing

No peer-reviewed case series or cohort study documenting this variant in affected individuals

Sources

clinvar ↗

PP1 The ClinVar submission SCV005046057 extracted a PP1 signal (2 cases in 1 pedigree: 1 bilateral, 1 unilateral), but this is from a single submitter with no validated publication trail. The evidence is insufficient to apply PP1 at any strength level in the absence of an independently verifiable published segregation study. Details ▾Hide ▴

Evidence considered

ClinVar submission reports 2 cases in 1 pedigree
but unverifiable without published study

Still missing

No published segregation analysis for this variant

Sources

clinvar ↗

PP3 REVEL and BayesDel scores are not available for this variant as it is a deletion, not a single nucleotide variant. SpliceAI predicts no significant splice impact (max delta score = 0.05). No computational evidence supports a damaging effect. Details ▾Hide ▴

Evidence considered

REVEL: not applicable (not SNV)
BayesDel: not applicable (not SNV)
SpliceAI: max delta 0.05 (no significant splice impact predicted)

Sources

spliceai ↗

PP5 This variant is classified as Pathogenic in ClinVar (Variation ID: 3236941) with review status 'criteria provided, single submitter' (1-star). Under the applicable PP5 rule, only ClinVar entries with 3-star expert panel review status qualify for PP5 at supporting strength. The single submitter classification does not meet this threshold. Details ▾Hide ▴

Evidence considered

ClinVar classification: Pathogenic
1-star (criteria provided
single submitter)
Does not meet 3-star expert panel threshold required for PP5 supporting

Sources

clinvar ↗

BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0.0%, which is well below the >1% BA1 threshold. Details ▾Hide ▴

Evidence considered

Allele frequency 0.0% in all gnomAD populations
far below BA1 threshold of >1%

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 This variant is absent from all gnomAD populations. The allele frequency is 0.0%, which is below the BS1 threshold of >0.3% for non-VCEP application. Details ▾Hide ▴

Evidence considered

Allele frequency 0.0% in all gnomAD populations
below BS1 threshold of >0.3%

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS3 No functional studies demonstrating a neutral or benign effect of this variant were identified. All reviewed publications address RB1 function at the gene level without testing NM_000321.2:c.1027_1028del specifically. Details ▾Hide ▴

Evidence considered

No variant-specific functional studies identified that demonstrate a benign effect

BP4 REVEL and BayesDel are not available (not SNV). SpliceAI predicts no significant splice impact (max delta 0.05). No computational evidence supports a benign effect, and no multiple lines of benign computational evidence exist. Details ▾Hide ▴

Evidence considered

REVEL: not applicable (not SNV)
BayesDel: not applicable (not SNV)
SpliceAI: max delta 0.05 (no splice impact)

Sources

spliceai ↗

BP6 ClinVar classifies this variant as Pathogenic, not Benign or Likely Benign. BP6 applies when a reputable source classifies the variant as benign. The ClinVar classification is Pathogenic, so BP6 is not met. Details ▾Hide ▴

Evidence considered

ClinVar classification is Pathogenic (not benign)
BP6 threshold not met

Sources

clinvar ↗

Not assessed · 7 · no assessment recorded

PS2 No de novo data available for this variant. No published studies or clinical reports documenting de novo occurrence were identified in the literature reviewed. Details ▾Hide ▴

Still missing

No de novo testing data available

PM6 No de novo data available for this variant. No published reports documenting de novo occurrence were identified. Details ▾Hide ▴

Still missing

No de novo testing data available

PP4 Patient phenotype data is not available in the case materials. PP4 requires that the patient's phenotype or family history is highly specific for the disease. Without access to the proband's clinical presentation, this criterion cannot be assessed. Details ▾Hide ▴

Still missing

Patient phenotype and family history data not available in the case materials

BS2 No data available regarding observation of this variant in healthy adult controls. The variant is absent from gnomAD, which precludes assessment of BS2. Details ▾Hide ▴

Still missing

No control cohort data available

BS4 No segregation data is available for this variant. BS4 requires evidence that the variant does not segregate with disease in affected family members. Details ▾Hide ▴

Still missing

No segregation data available

BP2 No data available regarding observation of this variant in trans with a known pathogenic variant. BP2 cannot be assessed without such evidence. Details ▾Hide ▴

Still missing

No data on in trans occurrence with pathogenic variants

BP5 No data available regarding observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴

Still missing

No data on alternate molecular basis

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 applies when the same amino acid change has been established as pathogenic via a different nucleotide change. This is a frameshift deletion introducing a premature termination codon, not a nucleotide substitution producing the same amino acid change. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped per directive. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants that change protein length without a null effect. This variant is a frameshift deletion predicted to cause NMD and complete loss of function, which is already captured by PVS1. PM4 is not applied in addition to PVS1 for the same variant under ACMG/AMP rules to avoid double-counting. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies when a different missense change at the same residue has been established as pathogenic. This is a frameshift deletion, not a missense variant. The PM5 candidate search confirmed no classic same-residue PM5 semantics are parseable from a frameshift variant. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes where missense variants are a common disease mechanism and benign missense variation is rare. This is a frameshift deletion, not a missense variant. Additionally, RB1 disease is primarily driven by truncating LOF variants, making PP2 inapplicable. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a frameshift truncating variant in RB1, where truncating LOF variants are the established disease mechanism. BP1 is inapplicable to truncating variants. 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 is a frameshift deletion, not an in-frame variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants predicted to have no splice impact. This is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/ASkipped per directive; not assessed. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: RB1
Transcript: NM_000321.2
Coding (HGVS c.): NM_000321.2:c.1027_1028del
Protein (HGVS p.): NP_000312.2:p.(Leu343SerfsTer3)
GRCh38: chr13:48367578 ACT>A
GRCh37: chr13:48941714 ACT>A
ClinVar: 3236941

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…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in RB1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

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 -84 bp

0.050

SpliceAI acceptor gainat -102 bp

0.010

SpliceAI donor lossat +25 bp

0.020

SpliceAI donor gainat +37 bp

0.000

Pangolin splice lossmagnitude shown

-0.110

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

REVEL: not applicable (not SNV)
BayesDel: not applicable (not SNV)
SpliceAI: max delta 0.05 (no significant splice impact predicted)

Sources

spliceai ↗

Evidence considered

REVEL: not applicable (not SNV)
BayesDel: not applicable (not SNV)
SpliceAI: max delta 0.05 (no splice impact)

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants predicted to have no 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 = 0.05).

9 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) methodology for detecting RB1 germline mutations in 27 retinoblastoma probands. Four kindreds had frameshift deletions detected by PTT, but NM_000321.2:c.1027_1028del is not individually reported.
Does not name this variant
PMID 14769601 ↗
RB1 mutations and second primary malignancies after hereditary retinoblastoma.

Retrospective cohort study of 199 hereditary retinoblastoma survivors evaluating whether specific RB1 germline mutations are associated with second primary malignancy risk. NM_000321.2:c.1027_1028del was not found in the full text.
Does not name this variant
PMID 22205104 ↗
Deletion of Rb1 induces both hyperproliferation and cell death in murine germinal center B cells.

Investigates consequences of conditional Rb1 deletion in murine germinal center B cells using mouse models. No human RB1 variant data 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.

Reports circulating tumor DNA analysis from the PALOMA-3 trial of palbociclib plus fulvestrant in ER+ breast cancer. RB1 mutations are discussed as a resistance mechanism, but NM_000321.2:c.1027_1028del is not reported.
Does not name this variant
PMID 30206110 ↗
RB1 Deletion in Retinoblastoma Protein Pathway-Disrupted Cells Results in DNA Damage and Cancer Progression.

Functional study using CRISPR/Cas9 to generate RB1 deletions in cancer cell lines to investigate DNA damage and genome instability. NM_000321.2:c.1027_1028del was not tested.
Does not name this variant
PMID 31138663 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

ACMG/AMP standards and guidelines for sequence variant interpretation. This is a methodological guideline describing the ACMG classification framework; it does not report specific variants.
Does not name this variant
PMID 25741868 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.

Trepanier A et al. · 2004

NSGC practice recommendations for cancer genetic risk assessment and counseling. Describes hereditary cancer syndromes and counseling processes. RB1 is listed in a table of rare hereditary cancer syndromes but no specific RB1 variants are discussed.
Does not name this variant
PMID 15604628 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.

Green RC et al. · 2013

ACMG recommendations for reporting incidental findings in clinical exome and genome sequencing. RB1 is listed among genes recommended for return of secondary findings, but no specific RB1 variants are discussed.
Does not name this variant
PMID 23788249 ↗
Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents.

Botkin JR et al. · 2015

Points to consider regarding ethical, legal, and psychosocial implications of genetic testing in children and adolescents. No specific gene variants are discussed.
Does not name this variant
PMID 26140447 ↗

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 0.050 Open source ↗

ClinVar 1 Pathogenic 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 has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 3236941)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).

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. COSMIC could not be reviewed because the browser session was redirected to the login page before search results were available.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.