Variant classification summary

NM_000321.2:c.275_282del

RB1 · NP_000312.2:p.(Ile92LysfsTer15) · NM_000321.2

GRCh37: chr13:48916744 ATTCAAAAG>A · GRCh38: chr13:48342608 ATTCAAAAG>A

Gene: RB1 Transcript: NM_000321.2

Final call

VUS

PM2 supporting

Variant details

Gene

RB1

Transcript

NM_000321.2

Protein

NP_000312.2:p.(Ile92LysfsTer15)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Uncertain Significance: PM2 (supporting) is met because the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets.

Final determination:

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	Not assessed	PVS1 could not be assessed because its agent did not produce valid output.
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000321.2:c.275_282del in RB1 is a frameshift variant predicted to produce NP_000312.2:p.(Ile92LysfsTer15). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband/parental trio or de novo confirmation data present in the case evidence.
PS3	Not assessed	Not assessed: no functional assay data specific to this exact RB1 frameshift variant was found in retrieved literature.
PS4	Not assessed	Not assessed: no case-control enrichment or odds-ratio data specific to this exact variant were available.
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000321.2:c.275_282del in RB1 is a frameshift variant predicted to produce NP_000312.2:p.(Ile92LysfsTer15). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met (supporting): variant absent from gnomAD v2.1, v4.1, and both non-cancer subsets, meeting PM2 absent/extremely-rare criteria.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: RB1 retinoblastoma is autosomal dominant, so the recessive-in-trans PM3 model does not apply and no proband phase data exists.
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000321.2:c.275_282del in RB1 is a frameshift variant predicted to produce NP_000312.2:p.(Ile92LysfsTer15). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000321.2:c.275_282del in RB1 is a frameshift variant predicted to produce NP_000312.2:p.(Ile92LysfsTer15). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no assumed-de-novo or parental data available to evaluate PM6.
PP1	Not assessed	Not assessed: no family segregation or meiosis data for this specific variant is available.
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000321.2:c.275_282del in RB1 is a frameshift variant predicted to produce NP_000312.2:p.(Ile92LysfsTer15). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: frameshift variant (p.Ile92LysfsTer15), outside the missense/splice-region scope of PP3.
PP4	Not assessed	Not assessed: no patient-specific phenotype or family history data for this variant were provided.
PP5	N/A	Not applicable: variant is absent from ClinVar, so no expert-panel classification exists to support PP5.	clinvar
BA1	Not met	Not met: variant absent from gnomAD v2.1/v4.1 (all-comers and non-cancer subsets), so allele frequency is 0, far below the BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: variant absent from all gnomAD releases (AF=0), well below the BS1 frequency threshold for RB1 disease prevalence.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: variant absent from all gnomAD cohorts, so no homozygous or unaffected-carrier observations exist to support BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional assay evidence of normal/benign protein activity exists for this frameshift variant.
BS4	Not assessed	Not assessed: no family segregation data available to evaluate non-segregation for BS4.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000321.2:c.275_282del in RB1 is a frameshift variant predicted to produce NP_000312.2:p.(Ile92LysfsTer15). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no proband genotype, second-variant, or trans/cis phase data are available anywhere in the case record.	clinvar
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000321.2:c.275_282del in RB1 is a frameshift variant predicted to produce NP_000312.2:p.(Ile92LysfsTer15). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: frameshift variant (p.Ile92LysfsTer15), outside the missense/splice-region scope of BP4.
BP5	Not assessed	Not assessed: no case data identifying an alternate molecular diagnosis for a carrier of this variant were available.
BP6	N/A	Not applicable: variant is absent from ClinVar, so no expert-panel benign classification exists to support BP6.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000321.2:c.275_282del in RB1 is a frameshift variant predicted to produce NP_000312.2:p.(Ile92LysfsTer15). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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