0%
RB1c.2341C>TUncertain significance
Print report
Variant interpretation report

RB1 c.2341C>T, p.(Pro781Ser)

NM_000321.2:c.2341C>T NP_000312.2:p.(Pro781Ser) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

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: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes), supporting moderate evidence for pathogenicity under the generic ACMG/AMP framework (allele frequency <0.1% in large population cohorts for a dominant disorder).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate; combination = 1 moderate, which maps to VUS.

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
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. 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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RB1, a regulator of the cell cycle, is inactivated by mutation, deletion or allelic loss in various cancer types, including retinoblastoma and lung ca

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV108030570, n = 1 times).

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.

26 criteria with recorded statuses: 1 met · 21 not met · 1 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PM2 is met at moderate strength: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada in a gene where pathogenic variants are expected to be rare.

BP1 is met at supporting benign strength: this is a missense variant in RB1, a gene where truncating variants are the primary disease mechanism (>80% of pathogenic variants are truncating per PMID:42461076).

Under the generic ACMG/AMP 2015 combination rules (PMID:25741868), one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP1) do not combine to reach any classification threshold. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 1

PM2 ModerateThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes), supporting moderate evidence for pathogenicity under the generic ACMG/AMP framework (allele frequency <0.1% in large population cohorts for a dominant disorder). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (AF = null
  • no observations).
  • Absent from gnomAD v4.1 (AF = null
  • Absent from gnomAD-Canada v1.0 (AF = 0.0
  • AC = 0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 21 · evaluated, threshold not reached

PS1 No evidence that the same amino acid change (Pro781Ser) has been previously established as pathogenic in an independent source. The variant is absent from ClinVar and no literature reports were identified linking this exact change to pathogenicity. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no prior pathogenic classification for P781S at this residue exists.
Still missing
  • No curated database or literature reports of P781S as a pathogenic change.
Sources
clinvar ↗
PS2 No de novo occurrence data (with confirmed maternity and paternity) was identified for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PS3 No variant-specific functional data is available. OncoKB reports unknown oncogenic effect with no reviewed functional evidence. COSMIC reports a single somatic occurrence but without functional characterization. No literature reports with experimental functional data for this exact variant or a systematically characterized range encompassing Pro781 were identified. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no reviewed functional evidence. COSMIC: 1 somatic occurrence (COSV108030570) without functional characterization.
Still missing
  • No experimental functional data for P781S or for a systematically characterized range that includes residue 781.
Sources
oncokb ↗
PS4 No case-control or cohort data demonstrating statistically increased prevalence of this variant in affected individuals versus controls. Details ▾Hide ▴
Still missing
  • No prevalence or case-control data available.
PM1 Position 781 (Pro781Ser) is in the RB1 C-terminal domain, not within a statistically significant mutational hotspot as defined by cancerhotspots.org. While the C-terminal domain is functionally relevant, no domain-level hotspot or critical functional motif specifically encompassing residue 781 is characterized in the available evidence to satisfy PM1. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org: residue 781 is not a significant hotspot. The C-terminal domain is functionally relevant but residue 781 is not within a characterized critical functional motif.
Still missing
  • Detailed domain-level characterization of Pro781 functional significance not available.
PM5 No same-residue comparator missense variants with an established pathogenic classification were identified. The automated PM5 candidate search returned zero eligible candidates at residue 781. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 same-residue candidates with expert-panel or majority pathogenic/likely pathogenic classification at Pro781.
Still missing
  • No comparator pathogenic missense variants at Pro781 identified.
Sources
pm5_candidates
PM6 No de novo occurrence was reported for this variant (without confirmation of paternity and maternity). Details ▾Hide ▴
Still missing
  • No de novo data available.
PP1 No co-segregation data in affected family members is available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data.
PP2 RB1 has both pathogenic and benign missense variants; it is not a gene with a low rate of benign missense variation. A large integrative study (PMID:42461076) reports that missense variants account for 9.2% of germline RB1 variants, indicating that missense variation is observed. Without evidence that benign missense variation is rare in RB1, PP2 does not apply. Details ▾Hide ▴
Evidence considered
  • PMID:42461076 reports missense variants comprise 9.2% of RB1 germline variants
  • RB1 is not established as having a low rate of benign missense variation.
Still missing
  • No RB1-specific missense constraint metric (e.g.
  • missense Z-score) available to formally exclude PP2.
PP3 In silico predictions are conflicting: REVEL scores 0.728 (damaging), but BayesDel scores -0.0665 (neutral/benign) and SpliceAI shows no splicing impact (max delta 0.01). Multiple lines of computational evidence do not agree on a deleterious effect, so PP3 is not met. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.728 (damaging).
  • BayesDel: -0.0665026 (neutral/benign direction).
  • SpliceAI: max delta 0.01 (no splice impact).
  • Conflicting predictions preclude PP3.
Sources
revelbayesdelspliceai ↗
PP4 No phenotype data is available for the proband(s) carrying this variant. The patient's clinical presentation relative to RB1-associated disease (retinoblastoma/osteosarcoma) cannot be assessed. Details ▾Hide ▴
Still missing
  • No proband phenotype information available.
PP5 This variant is absent from ClinVar. No reputable source (expert panel, clinical laboratory) has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entry found for c.2341C>T in RB1.
Still missing
  • Not reported in ClinVar.
Sources
clinvar ↗
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Variant is absent from all population databases
  • AF = 0.0
  • far below BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from all population databases. Allele frequency of 0% does not exceed the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Variant is absent from all population databases
  • AF = 0.0
  • far below BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No data is available demonstrating this variant has been observed in healthy adults. Absence from gnomAD is insufficient to confirm observation in healthy individuals for a dominant disorder. Details ▾Hide ▴
Still missing
  • No reports of this variant in healthy adult carriers.
BS3 No functional studies demonstrating a benign effect for this variant are available. OncoKB reports unknown oncogenic effect with no reviewed functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB: no reviewed functional evidence available
  • unknown oncogenic effect.
Still missing
  • No functional data demonstrating benign or neutral effect.
Sources
oncokb ↗
BS4 No segregation data demonstrating lack of co-segregation with disease is available. Details ▾Hide ▴
Still missing
  • No family segregation data.
BP2 No data is available showing this variant is observed in trans with a known pathogenic RB1 variant, which would support benign classification for a dominant disorder. Details ▾Hide ▴
Still missing
  • No trans-phase data available.
BP4 In silico predictions are conflicting. REVEL scores 0.728 (damaging), which precludes BP4. Multiple lines of computational evidence do not agree on a benign or neutral effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.728 (damaging)
  • inconsistent with BP4.
  • BayesDel: -0.0665026 (neutral).
  • SpliceAI: max delta 0.01 (no splice impact).
  • Predictions are not concordant for a benign effect.
Sources
revelbayesdelspliceai ↗
BP5 No data is available demonstrating this variant is found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No cases with alternate molecular diagnosis reported.
BP6 This variant is absent from ClinVar. No reputable source has classified it as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entry found
  • no benign classification from any submitter.
Still missing
  • Not reported in ClinVar.
Sources
clinvar ↗

Not assessed · 1 · no assessment recorded

BP1 This is a missense variant in RB1, a gene for which truncating variants are the primary known disease mechanism. A large integrative analysis (PMID:42461076) reports that truncating germline variants account for >80% of pathogenic RB1 variants, while missense variants comprise only 9.2%. BP1 applies at supporting benign strength. Details ▾Hide ▴
Evidence considered
  • PMID:42461076 (2026): Truncating germline RB1 variants account for >80% of pathogenic/likely pathogenic variants
  • missense variants are a minority mechanism.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.2341C>T, p.Pro781Ser); it does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense substitution is not a null variant type eligible for PVS1 under the generic framework.
Sources
pvs1_generic_framework ↗
BP7 N/AThis is a missense variant (c.2341C>T, p.Pro781Ser), not a synonymous or intronic variant. BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion. No evidence framework defines applicability for this code in the generic ACMG context. Details ▾Hide ▴
Evidence considered
  • Not a recognized ACMG/AMP 2015 criterion.

Identifiers

Gene
RB1
Transcript
NM_000321.2
Coding (HGVS c.)
NM_000321.2:c.2341C>T
Protein (HGVS p.)
NP_000312.2:p.(Pro781Ser)
GRCh38
chr13:48465220 C>T
GRCh37
chr13:49039356 C>T
COSMIC
COSV108030570

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 +331 bp
0.000
SpliceAI acceptor gainat -15 bp
0.000
SpliceAI donor lossat +422 bp
0.000
SpliceAI donor gainat +148 bp
0.010
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.010

Other predictors

REVEL
0.728
BayesDel
-0.067

How the predictions were used

PP3 In silico predictions are conflicting: REVEL scores 0.728 (damaging), but BayesDel scores -0.0665 (neutral/benign) and SpliceAI shows no splicing impact (max delta 0.01). Multiple lines of computational evidence do not agree on a deleterious effect, so PP3 is not met. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.728 (damaging).
  • BayesDel: -0.0665026 (neutral/benign direction).
  • SpliceAI: max delta 0.01 (no splice impact).
  • Conflicting predictions preclude PP3.
Sources
revelbayesdelspliceai ↗
BP4 In silico predictions are conflicting. REVEL scores 0.728 (damaging), which precludes BP4. Multiple lines of computational evidence do not agree on a benign or neutral effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.728 (damaging)
  • inconsistent with BP4.
  • BayesDel: -0.0665026 (neutral).
  • SpliceAI: max delta 0.01 (no splice impact).
  • Predictions are not concordant for a benign effect.
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.2341C>T, p.Pro781Ser), not a synonymous or intronic variant. BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.728. BayesDel score = -0.0665026.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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 0.010 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 = 0.01). REVEL score = 0.728. BayesDel score = -0.0665026.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RB1, a regulator of the cell cycle, is inactivated by mutation, deletion or allelic loss in various cancer types, including retinoblastoma and lung ca

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV108030570, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.