Variant classification summary

NM_000321.3:c.2165A>G

RB1 · NP_000312.2:p.(Lys722Arg) · NM_000321.3

GRCh37: chr13:49037925 A>G · GRCh38: chr13:48463789 A>G

Gene: RB1 Transcript: NM_000321.3

Final call

VUS

PM2 supporting

Variant details

Gene

RB1

Transcript

NM_000321.3

Protein

NP_000312.2:p.(Lys722Arg)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, supporting population rarity.

2

With only one supporting pathogenic criterion and no benign criteria, no combination threshold is met; the variant is classified as VUS.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: this missense substitution triggers no null-variant mechanism such as nonsense-mediated decay or truncation.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Insufficient evidence was available to assess whether this exact amino-acid change has been previously reported as pathogenic.
PS2	Not assessed	Not assessed: no de novo observation or parental-testing results were available.
PS3	Not assessed	Not assessed: no validated functional assay results for this variant were available.
PS4	Not assessed	Not assessed: no case-control or cohort prevalence data for this exact variant were available.
PM1	Not assessed	Insufficient evidence was available to assess whether this variant falls in a mutational hotspot or critical domain.
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: RB1-associated retinoblastoma is autosomal dominant, so this recessive-phase criterion does not apply.	PMID:27854360
PM4	N/A	Not applicable: this missense substitution causes no change in protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Insufficient evidence was available to assess whether a different pathogenic missense change exists at this same codon.
PM6	Not assessed	Not assessed: no suspected de novo occurrence with confirmed parental testing was documented.
PP1	Not assessed	Not assessed: no family segregation data (affected or unaffected relatives) were available.
PP2	Not assessed	Insufficient evidence was available to assess the gene's rate of benign missense variation.
PP3	Not met	Not met: REVEL score 0.703 falls in the gray zone and does not meet the pathogenic threshold.	revel spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no phenotype, diagnostic, or family-history data for a carrier were available.	clinvar
PP5	Not met	Not met: no ClinVar expert-panel Pathogenic or Likely pathogenic assertion exists for this exact variant.	clinvar
BA1	Not met	Not met: the variant is absent from population databases, far below the >5% allele-frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from population databases, so no allele frequency above that expected for RB1-related disease is shown.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no unaffected-adult cohort or healthy-homozygote observations were available.
BS3	Not assessed	Not assessed: no well-established assay demonstrating normal function of this variant was available.
BS4	Not assessed	Not assessed: no family segregation or unaffected-relative data were available.
BP1	Not assessed	Insufficient evidence was available to assess whether this gene causes disease only through truncating variants.
BP2	Not assessed	Not assessed: no parental testing or phase information was available to establish an in-trans observation.	PMID:27854360
BP3	N/A	Not applicable: this criterion covers in-frame indels in repetitive regions, not missense substitutions.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL score 0.703 falls in the gray zone and does not meet the benign threshold.	revel spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no data establishing an alternate molecular cause of the phenotype were available.
BP6	Not met	Not met: no ClinVar expert-panel Benign or Likely benign assertion exists for this exact variant.	clinvar
BP7	N/A	Not applicable: this criterion applies only to synonymous variants; this is a missense substitution.	generic_acmg_combination_rules

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