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RB1
Final classification
VUS
PM2
RB1
c.2165A>G
p.Lys722Arg
missense · exon 21
Gene context NCBI Gene ↗ OncoKB ↗

RB1 encodes a protein that acts as a key brake on cell division: in its active form it blocks cells from moving from the G1 into the S phase of the cell cycle, and it also helps maintain the structure of packaged DNA in the nucleus. It was the first tumor suppressor gene identified. Loss of RB1 function removes this brake, leading to uncontrolled cell growth and contributing to many cancers, including retinoblastoma (a childhood eye cancer), bladder cancer, osteogenic sarcoma, and cancers of the lung, breast, and prostate. Inherited changes in RB1 predispose children to retinoblastoma and adults to sarcomas and other tumors.

This variant

RB1 is a tumor-suppressor gene whose loss removes the brake on cell division and drives retinoblastoma and other cancers. This missense change (p.Lys722Arg) is classified as a variant of uncertain significance: current evidence neither demonstrates nor excludes a damaging effect on RB1's tumor-suppressor function.

Transcript
NM_000321.3
HGVS · transcript:coding
NM_000321.3:c.2165A>G
GRCh38
chr13:48463789 A>G
GRCh37
chr13:49037925 A>G
Basis No RB1-specific framework was available, so generic ACMG/AMP 2015 rules applied; the only met criterion, PM2 at supporting strength, does not reach a Likely Pathogenic/Pathogenic combination, and no benign criteria were met. ▾
No RB1-specific framework was available, so generic ACMG/AMP 2015 rules applied; the only met criterion, PM2 at supporting strength, does not reach a Likely Pathogenic/Pathogenic combination, and no benign criteria were met.
Classification rationale
PM2 VUS
RB1 c.2165A>G missense · exon 21

PM2 (Supporting): variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, supporting population rarity. With only one supporting pathogenic criterion and no benign criteria, no combination threshold is met; the variant is classified as VUS.

PM2 → VUS
Gene diagram · NM_000321.3 · variants mapped to exon structure
RB1 NM_000321.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 22 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 · 1
Strength Supporting Moderate Strong Very strong
✓
PM2 supporting Pathogenic
Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases.
The consolidated evidence bundle reports the exact variant NM_000321.3:c.2165A>G (NP_000312.2:p.(Lys722Arg)) as absent from gnomAD v2.1.The consolidated evidence bundle reports the exact variant as absent from gnomAD v4.1.The consolidated evidence bundle reports the exact variant as absent from gnomAD-Canada v1.0.
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 6 not met · 16 not assessed
Pathogenic
PS1 Insufficient evidence was available to assess whether this exact amino-acid change has been previously reported as pathogenic.
PS2 Not assessed: no de novo observation or parental-testing results were available.
PS3 Not assessed: no validated functional assay results for this variant were available.
PS4 Not assessed: no case-control or cohort prevalence data for this exact variant were available.
PM1 Insufficient evidence was available to assess whether this variant falls in a mutational hotspot or critical domain.
PM5 Insufficient evidence was available to assess whether a different pathogenic missense change exists at this same codon.
PM6 Not assessed: no suspected de novo occurrence with confirmed parental testing was documented.
PP1 Not assessed: no family segregation data (affected or unaffected relatives) were available.
PP2 Insufficient evidence was available to assess the gene's rate of benign missense variation.
PP3 Not met: REVEL score 0.703 falls in the gray zone and does not meet the pathogenic threshold.
PP4 Not assessed: no phenotype, diagnostic, or family-history data for a carrier were available.
PP5 Not met: no ClinVar expert-panel Pathogenic or Likely pathogenic assertion exists for this exact variant.
Benign
BA1 Not met: the variant is absent from population databases, far below the >5% allele-frequency threshold.
BS1 Not met: absent from population databases, so no allele frequency above that expected for RB1-related disease is shown.
BS2 Not assessed: no unaffected-adult cohort or healthy-homozygote observations were available.
BS3 Not assessed: no well-established assay demonstrating normal function of this variant was available.
BS4 Not assessed: no family segregation or unaffected-relative data were available.
BP1 Insufficient evidence was available to assess whether this gene causes disease only through truncating variants.
BP2 Not assessed: no parental testing or phase information was available to establish an in-trans observation.
BP4 Not met: REVEL score 0.703 falls in the gray zone and does not meet the benign threshold.
BP5 Not assessed: no data establishing an alternate molecular cause of the phenotype were available.
BP6 Not met: no ClinVar expert-panel Benign or Likely benign assertion exists for this exact variant.
N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from 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 screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1786969)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.703. BayesDel score = 0.121025.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
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
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
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 ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 5 PMIDs not cited in assessment
15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR
25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR
27854360 ↗ Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. CLINVAR
35802134 ↗ ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR
26140447 ↗ Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents. CLINVAR