BCOR c.3870_3871insC, p.(Lys1291GlnfsTer84)

Reasoning

NM_017745.5:c.3870_3871insC in BCOR is a 1-nt insertion producing a frameshift, NP_060215.4:p.(Lys1291GlnfsTer84), a null-variant class per the ClinGen SVI PVS1 decision tree (PMC6185798). The variant lies in exon 9 of 15 (c.3746-4071); the premature termination codon at p.1374 (~c.4120, exon 10) is 753 nt upstream of the final exon-exon junction (exon 14/15 at c.4875), well beyond the 50-55 nt NMD threshold, so NMD is predicted and the variant is not in the last exon or last 50 bp of the penultimate exon - full-strength PVS1 is not excluded on NMD grounds. Gene-level loss-of-function is an established mechanism: BCOR is essential for human development and heterozygous germline LOF mutations cause oculofaciocardiodental (OFCD) syndrome (PMID:26847029), and the pipeline gene-context gate (pvs1_gene_context) was 'eligible'. The frameshift truncates the C-terminus (1722 -> 1374 aa, ~20% of the protein lost plus 84 novel out-of-frame residues), removing the region required for interaction with core PRC1 components; PMID:26847029 shows that Bcor alleles generating such C-terminally truncated proteins 'mimic the pathogenic mutations seen in OFCD patients'. No population LoF tolerance signal exists (absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0), and the variant is not in a repeat/low-complexity region that would suggest artefact or tolerance. No BCOR-specific CSPEC/VCEP exists, so the generic SVI PVS1 framework was applied; none of the standard downgrade considerations (NMD escape, last-exon location, non-critical distal region, exon enriched for population LoF) apply. PVS1 met at very strong.

Rule

PVS1: null variant (frameshift) + LOF is known disease mechanism + NMD predicted + not last exon/penultimate-exon-50bp (generic ClinGen SVI PVS1 decision tree, PMC6185798)

Evidence considered

• Frameshift consequence: Mutalyzer/VariantValidator normalization of NM_017745.5:c.3870_3871insC predicts NP_060215.4:p.(Lys1291GlnfsTer84) (wild-type protein 1722 aa; mutant protein 1374 aa with 84 novel out-of-frame residues), i.e., a null-variant class satisfying the first SVI PVS1 prerequisite.
• NMD prediction: the PTC at p.1374 (~c.4120, exon 10) is 753 nt upstream of the final exon-exon junction (exon 14/15 boundary at c.4875), far exceeding the 50-55 nt NMD threshold; the variant is in exon 9 of 15, not the last exon or the last 50 bp of the penultimate exon, so full-strength PVS1 is not excluded on NMD or location grounds.
• Gene-level LOF mechanism: pvs1_gene_context gate is 'eligible' (generic fallback; no BCOR CSPEC/VCEP). PMID:26847029 states 'The X-linked BCOR gene is essential for human development. Female patients harboring heterozygous mutations in BCOR develop oculofaciocardiodental (OFCD) syndrome', establishing BCOR LOF as a germline disease mechanism.
• Critical-region impact: the frameshift truncates the C-terminal ~348 aa, removing the region required for interaction with core PRC1 components; PMID:26847029 reports that a Bcor allele lacking exons 9-10 generating a truncated protein missing this region 'mimics the pathogenic mutations seen in OFCD patients'.
• No population LoF tolerance signal: the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, providing no evidence that the affected exon tolerates null variation, so no PVS1 downgrade for population LoF enrichment.
• Somatic LOF context: PMID:24047651 found 15 BCOR truncating mutations in MDS (8 frameshift, 5 nonsense, 2 splice-site) plus frameshift/nonsense BCORL1 mutations, with truncating BCOR mutations associated with worse overall survival and higher AML transformation, consistent with LOF as the operative mechanism.
• OncoKB variant-specific annotation for K1291Qfs*84 gives biological effect 'Likely Loss-of-function' (oncogenicity 'Likely Oncogenic'), corroborating the predicted functional effect of this frameshift.
• No repeat-region or low-complexity annotation flags this insertion site; no artefact-prone homopolymer context identified that would question the frameshift interpretation.

Still missing

• No BCOR-specific CSPEC/VCEP exists; PVS1 was calibrated with the generic ClinGen SVI framework (PMC6185798) only.
• NM_017745.5 is not flagged MANE Select or RefSeq Select by VariantValidator (NM_017745.6 is the newer RefSeq version); full-strength PVS1 is retained because the frameshift is mid-gene, NMD-predicted, and removes the C-terminal PRC1-interaction region, but the equivalent position on the MANE transcript should be confirmed to keep full strength.
• No functional assay directly testing this exact variant (c.3870_3871insC) is available; the LOF effect is inferred from consequence class, NMD prediction, and truncation of the C-terminal PRC1-interaction region.

Sources

Reasoning

PM2 is met: the variant is absent (AF = 0) from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, i.e. absent in controls / at an extremely low allele frequency, well below this lab's non-VCEP PM2 operating threshold of AF < 0.1%. BCOR is an X-linked gene (Xp11.4) with a supported germline loss-of-function disease mechanism, so absence in population controls, including male hemizygotes, supports a pathogenic role. Under the generic ACMG/AMP 2015 framework PM2 contributes supporting strength. Confidence is moderate rather than high because the variant is a single-base insertion (c.3870_3871insC) that short-read sequencing can under-call in homopolymer/repetitive contexts; the consistent absence across two gnomAD builds plus gnomAD-Canada mitigates but does not fully eliminate this technical artifact risk.

Rule

PM2: absent in controls / extremely low allele frequency in population databases (Richards et al. 2015, PMID:25741868); lab non-VCEP gnomAD operating threshold PM2 < 0.1%

Evidence considered

• gnomAD v2.1 (exome, GRCh37): variant X-39922199-T-TG absent (search_status 'absent', AF = 0).
• gnomAD v4.1 (exome, GRCh38): variant X-40062946-T-TG absent (search_status 'absent', AF = 0).
• gnomAD-Canada v1.0 (HostSeq genomes): variant X-40062946-T-TG absent (search_status 'absent', AF = 0).
• PM2 semantics per Richards et al. 2015 (PMID:25741868): absent in controls / extremely low frequency in population databases (ExAC/1000G/ESP); observed AF of 0 across gnomAD v2.1, v4.1, and gnomAD-Canada satisfies the criterion at supporting strength.
• BCOR is X-linked (Xp11.4, OMIM 300485); hemizygous males are included in gnomAD allele counts, so absence also covers the hemizygous state relevant to an X-linked disorder.

Still missing

• Single-base insertion may be under-detected by short-read sequencing in repetitive/homopolymer contexts; absence was confirmed across three independent datasets (gnomAD v2.1, v4.1, gnomAD-Canada), but site-level QC flags (e.g. AC0 filter status) were not individually reviewed.
• No gnomAD constraint metric (e.g. LOEUF/pLI) or gene-level LoF tolerance assessment was available in the case bundle to contextualize PM2 strength.

Sources

Reasoning

Under the governing generic ACMG/AMP 2015 fallback PP3/BP4 rule (no ClinGen CSPEC/VCEP or gene-specific specification for BCOR), this non-missense (frameshift insertion) variant is evaluated with SpliceAI only. SpliceAI max delta score is 0.074, which is < 0.1, meeting the generic fallback BP4 threshold (SpliceAI max delta < 0.1 -> BP4 supporting) and consistent with the low-impact range of the SpliceAI publication (Jaganathan et al., Nat Genet 2019; PMID 30661751). No REVEL score is available and none is used, per the generic rule that a non-missense variant has no REVEL score and there is no fallback to the missense-path predictor. NOTE for human review: this BP4 reflects only the splice-impact sub-path (no predicted splice disruption); it does not indicate that the gene product is unaffected, since the variant's coding consequence is a frameshift truncation (p.Lys1291GlnfsTer84) evaluated under PVS1 by another group. The final classification must not treat this BP4 as contradicting the frameshift loss-of-function consequence.

Rule

BP4 (ACMG/AMP 2015; generic fallback non-missense branch: SpliceAI max delta < 0.1 -> BP4 supporting)

Evidence considered

• SpliceAI (source key: spliceai) max delta score 0.074 is < 0.1, meeting the generic ACMG fallback BP4 threshold for non-missense variants (source key: generic_acmg_combination_rules: SpliceAI max delta < 0.1 -> BP4 supporting); the low score is consistent with the low-impact range of the SpliceAI publication (Jaganathan et al., Nat Genet 2019; PMID 30661751).
• BP4 here reflects only the splice-impact sub-path (no predicted splice disruption); the variant's coding consequence is a frameshift (p.Lys1291GlnfsTer84) evaluated by other groups (PVS1), so this BP4 must not be read as evidence that the gene product is unaffected.
• No REVEL score is available and none is used: per the generic rule, a non-missense variant has no REVEL score and there is no fallback to the missense-path predictor for the wrong variant type.

Still missing

• BP4 application to a frameshift variant is unusual: the code reflects only absence of predicted splice disruption and does not speak to the protein-level truncation; confirm at final classification that BP4 is not interpreted as evidence against the frameshift LoF consequence (PVS1).
• The 0.1 BP4 boundary is the lab's operating threshold defined in generic_acmg_combination_rules (SVI-recommended SpliceAI thresholds, cf. Walker et al. 2023); no gene-specific calibration exists for BCOR.

Sources

Reasoning

PS4 requires a significantly increased prevalence of the variant in affected individuals compared with controls (Richards et al. 2015, PMID 25741868). No case-control or cohort enrichment data exist for the exact variant NM_017745.5:c.3870_3871insC (p.(Lys1291GlnfsTer84)): ClinVar has no record for it, the five retrieved BCOR publications (somatic AML/MDS/retinoblastoma cohorts) do not report this exact variant, and OncoKB's 'Likely Oncogenic / Likely Loss-of-function' annotation is a somatic oncology label, not germline case-control enrichment evidence. PS4 is therefore not met.

Rule

PS4: Prevalence of variant in affected individuals significantly increased compared with controls (Richards et al. 2015, PMID 25741868)

Evidence considered

• Generic ACMG/AMP 2015 (Richards et al., PMID 25741868) governs this case because no ClinGen CSPEC/VCEP specification exists for BCOR (framework_mode=generic_acmg, framework_complete=false).
• ClinVar was searched with six term variants (BCOR[GENE] AND c.3870_3871insC[VARNAME], NM_017745.5:c.3870_3871insC[VARNAME], NM_017745.5:c.3870_3871insC, NC_000023.10:g.39922199_39922200insG[VARNAME], NC_000023.10:g.39922199_39922200insG, BCOR[GENE] AND NM_017745.5:c.3870_3871insC); exact_match=false and variation_ids=[] - no record exists, so no affected-individual prevalence data from ClinVar.
• OncoKB reports BCOR p.K1291Qfs*84 as 'Likely Oncogenic' with 'Likely Loss-of-function' biological effect; this is a variant-specific somatic oncology curation, not a germline case-control enrichment study, and cannot satisfy PS4.
• Searched all five retrieved BCOR full texts (PMID:22012066, PMID:22237022, PMID:24047651, PMID:25550361, PMID:26847029) for the exact variant (c.3870_3871insC, 3870/3871, K1291, Lys1291, Qfs*84, insC); none report this exact variant, so no case-control enrichment evidence for this variant is available from the retrieved literature.

Still missing

• No case-control or cohort study reporting this exact variant (c.3870_3871insC) in affected individuals versus controls

Sources

Reasoning

Variant NM_017745.5:c.3870_3871insC (BCOR) is a frameshift insertion (p.Lys1291GlnfsTer84), i.e. a non-missense variant, so under the governing generic ACMG/AMP 2015 fallback rule (no ClinGen CSPEC/VCEP or gene-specific PP3/BP4 specification exists for BCOR) only the SpliceAI splice-impact path is evaluated. SpliceAI reports max delta score 0.074 (DS_AG 0.074, DS_AL 0.018, DS_DG 0.030, DS_DL 0.002), which is below the 0.2 splice-altering threshold from the SpliceAI publication (Jaganathan et al., Nat Genet 2019; PMID 30661751) and below the generic fallback's PP3 threshold (SpliceAI max delta > 0.2). No computational evidence therefore supports a deleterious splice effect; the missense in-silico path (REVEL/BayesDel) is not applicable to a non-missense variant (predictor pipeline skipped: not an SNV) and per the generic rule there is no cross-predictor fallback. PP3 is not met.

Rule

PP3 (ACMG/AMP 2015; generic fallback non-missense branch: SpliceAI max delta > 0.2 -> PP3 supporting)

Evidence considered

• SpliceAI (source key: spliceai) reports max delta score 0.074 (DS_AG 0.074, DS_AL 0.018, DS_DG 0.030, DS_DL 0.002) for NM_017745.5:c.3870_3871insC, below the 0.2 splice-altering threshold recommended in the SpliceAI publication (Jaganathan et al., Nat Genet 2019; PMID 30661751); no splice-impact evidence supports PP3.
• Variant is a frameshift insertion (non-missense); per the generic ACMG fallback PP3/BP4 rule (source key: generic_acmg_combination_rules) non-missense variants are evaluated with SpliceAI only, and REVEL/BayesDel are not applicable (predictor pipeline skipped: not an SNV).
• No ClinGen CSPEC/VCEP or gene-specific PP3/BP4 lookup exists for BCOR; generic ACMG/AMP 2015 (Richards et al., PMID 25741868) governs.

Still missing

• No ClinGen CSPEC/VCEP or gene-specific PP3/BP4 specification for BCOR; generic ACMG/AMP 2015 fallback used (output/generic_acmg_classification_rules.md).
• Missense in-silico predictors (REVEL/BayesDel) are not applicable to this frameshift insertion; only the splice-impact sub-path was evaluable for PP3.

Sources

Reasoning

PP5 is applied only when an exact-variant ClinVar expert-panel (3-star) classification of Pathogenic/Likely pathogenic exists. NM_017745.5:c.3870_3871insC is absent from ClinVar entirely (exact_match=false, variation_ids=[] across all search term variants), so no expert-panel classification of any kind exists for this variant. There is therefore no basis to apply PP5, and it is not met.

Rule

PP5: Reputable source reports variant as pathogenic without independent evaluation - restricted to exact-variant ClinVar expert-panel (3-star) classifications

Evidence considered

• ClinVar has no record for NM_017745.5:c.3870_3871insC (no variation ID, no submissions, no review status); no exact-variant ClinVar expert-panel classification exists to support PP5.
• Policy: PP5 requires a ClinVar 3-star expert-panel Pathogenic/Likely pathogenic classification of the exact variant; absent here, so PP5 is not met regardless of any other source's assertions.

Sources

Reasoning

BA1 requires an allele frequency greater than 5% in reference population databases (Richards et al. 2015, PMID:25741868); this lab's non-VCEP gnomAD operating threshold for BA1 is AF > 1%. NM_017745.5:c.3870_3871insC (BCOR, Xp11.4) is absent from gnomAD v2.1 (GRCh37 X-39922199-T-TG), gnomAD v4.1 (GRCh38 X-40062946-T-TG), and gnomAD-Canada v1.0, i.e. observed allele frequency is 0 in every queried population dataset. A frequency of 0 is orders of magnitude below any BA1 threshold, so the stand-alone benign criterion cannot be met.

Rule

BA1: allele frequency > 5% in reference population databases (Richards et al. 2015, PMID:25741868); lab non-VCEP gnomAD operating threshold BA1 > 1%

Evidence considered

• gnomAD v2.1 (exome, GRCh37): variant X-39922199-T-TG queried by direct variant URL; search_status 'absent', no allele counts returned.
• gnomAD v4.1 (exome, GRCh38): variant X-40062946-T-TG queried by direct variant URL; search_status 'absent', no allele counts returned.
• gnomAD-Canada v1.0 (HostSeq genomes): variant X-40062946-T-TG queried via API; search_status 'absent'.
• BA1 threshold per Richards et al. 2015 (PMID:25741868): allele frequency > 5% in general population databases; observed AF of 0 does not approach this threshold.

Sources

Reasoning

BS1 requires an allele frequency greater than expected for the disorder. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (AF = 0 in all datasets), which is below any plausible disease-expected frequency and below this lab's non-VCEP gnomAD BS1 operating threshold of AF > 0.3%. With zero population observations, BS1 cannot be met.

Rule

BS1: allele frequency greater than expected for the disorder (Richards et al. 2015, PMID:25741868); lab non-VCEP gnomAD operating threshold BS1 > 0.3%

Evidence considered

• gnomAD v2.1 (exome, GRCh37): variant X-39922199-T-TG absent (search_status 'absent').
• gnomAD v4.1 (exome, GRCh38): variant X-40062946-T-TG absent (search_status 'absent').
• gnomAD-Canada v1.0 (HostSeq genomes): variant X-40062946-T-TG absent (search_status 'absent').
• BS1 semantics per Richards et al. 2015 (PMID:25741868): allele frequency greater than expected for the disorder; observed AF of 0 is below every expected-frequency estimate for a rare X-linked loss-of-function phenotype.

Sources

Reasoning

BS2 requires observation of the variant in a healthy adult (hemizygous in an X-linked disorder such as BCOR-associated disease). No such observation exists: the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (large population/control cohorts), and ClinVar contains no submission for this variant (no healthy or affected individuals reported). Absence of any healthy-adult observation means BS2 is not met.

Rule

BS2: observed in a healthy adult individual (hemizygous for X-linked disorders) (Richards et al. 2015, PMID:25741868)

Evidence considered

• gnomAD v2.1: variant absent; no hemizygous or heterozygous carrier observations in this population cohort.
• gnomAD v4.1: variant absent; no carrier observations in this population cohort.
• gnomAD-Canada v1.0: variant absent; no carrier observations in this population cohort.
• ClinVar: no submission found for BCOR c.3870_3871insC (searched by gene+var name and by genomic HGVS); no healthy-adult observations reported.
• BS2 semantics per Richards et al. 2015 (PMID:25741868): observed in a healthy adult individual for a dominant/X-linked disorder (heterozygous/hemizygous); no such observation is present in the available data.

Still missing

• No dedicated healthy-adult clinical cohort beyond gnomAD/ClinVar was available; the not_met determination rests on population-database and ClinVar absence rather than an explicitly phenotyped healthy control cohort.

Sources

Reasoning

BP6 is applied only when an exact-variant ClinVar expert-panel (3-star) classification of Benign/Likely benign exists. NM_017745.5:c.3870_3871insC is absent from ClinVar entirely (exact_match=false, variation_ids=[] across all search term variants), so no expert-panel classification of any kind exists for this variant. There is therefore no basis to apply BP6, and it is not met.

Rule

BP6: Reputable source reports variant as benign without independent evaluation - restricted to exact-variant ClinVar expert-panel (3-star) classifications

Evidence considered

• ClinVar has no record for NM_017745.5:c.3870_3871insC (no variation ID, no submissions, no review status); no exact-variant ClinVar expert-panel classification exists to support BP6.
• Policy: BP6 requires a ClinVar 3-star expert-panel Benign/Likely benign classification of the exact variant; absent here, so BP6 is not met regardless of any other source's assertions.

Sources

Reasoning

PS2 requires a de novo occurrence (maternity and paternity confirmed) in a proband with the disease and no family history. The case bundle contains no proband-level data at all: no proband phenotype or family history, no parental testing, and no maternity/paternity confirmation. The variant is absent from ClinVar (no curated de novo observations) and absent from gnomAD v2.1/v4.1/Canada. Full-text search of all 5 available publications (somatic cancer/functional studies retrieved via OncoKB) found no de novo or parentage-based evidence for this variant. Under the governing generic ACMG/AMP 2015 framework (no BCOR CSPEC/VCEP exists), PS2 cannot be evaluated without a confirmed de novo observation, so it is not assessed.

Rule

PS2 (ACMG/AMP 2015, Richards et al. PMID 25741868): De novo (maternity and paternity confirmed) occurrence in a proband with the disease and no family history.

Evidence considered

• Governing framework: no ClinGen CSPEC/VCEP exists for BCOR and no local gene-specific framework is present (framework_mode=generic_acmg), so generic ACMG/AMP 2015 criteria definitions (Richards et al. 2015, PMID 25741868) apply to PS2/PM6/PP1/BS4.
• ClinVar search (BCOR[GENE] AND c.3870_3871insC and multiple HGVS/allelic synonyms) returned no result; the evidence sentence in case_summary states 'This variant is absent from ClinVar.', so no de novo or segregation observations with proband/parental data exist in ClinVar.
• No proband, pedigree, parental testing, or family history data appear in review_manifest.json, case_summary.json, prefetch.json, evidence.json, or vcep_materials.json.
• Full-text search of the 5 available publications (PMID 22012066, 22237022, 24047651, 25550361, 26847029) for terms including 'de novo', 'denovo', 'segregat', 'maternity', 'paternity', 'proband', 'pedigree', 'family', 'germline', 'inherited', 'mosaic', 'parental' returned zero matches; these are somatic cancer cohort and functional studies with no proband-level de novo data for this variant.
• The literature_pass.json criteria_index and candidate_criteria are empty for all 5 papers; no paper was screened as segregation/case-observation evidence.

Still missing

• No proband carrying c.3870_3871insC with phenotype/family history is described in any source in the case bundle.
• No parental testing or maternity/paternity confirmation data are available.
• Variant is absent from ClinVar, so no curated de novo observation (with confirmed parentage) can be retrieved.

Sources

Reasoning

PS3 (Richards et al. 2015, ACMG/AMP, PMID:25741868) requires well-established functional studies demonstrating a deleterious effect of the variant. No variant-specific functional assay for NM_017745.5:c.3870_3871insC (p.Lys1291GlnfsTer84, BCOR) is present in the evidence bundle. The five OncoKB-sourced functional-theme papers (PMID:22012066, PMID:22237022, PMID:24047651, PMID:25550361, PMID:26847029) were read in full text: none mentions this variant or residue Lys1291, so none can support variant-specific PS3 under strict citation grounding. They provide only gene/class-level BCOR loss-of-function evidence (mouse Bcor conditional knockout with frameshift/premature stop, siRNA knockdown in HL60/NB4, and decreased BCOR mRNA/protein in AML/MDS cohorts carrying other disruptive BCOR mutations), which supports the LoF mechanism of the gene rather than a functional effect of this specific allele. OncoKB's variant-specific record labels the biological effect 'Likely Loss-of-function' and oncogenicity 'Likely Oncogenic', but this is a curated bioinformatic inference from the truncating consequence, not a validated functional assay, and a source's final classification cannot be used to infer a criterion. SpliceAI (max delta 0.074) is an in silico splice prediction, not a functional study. PS3 is therefore not assessable from available evidence; the gap is absence of any assay performed on this exact variant.

Rule

generic_acmg_2015_ps3

Evidence considered

• PS3 under generic ACMG/AMP 2015 (PMID:25741868) requires well-established functional studies showing a deleterious effect of the variant; no such study of c.3870_3871insC was retrieved.
• All five OncoKB-sourced functional-theme papers (PMID:22012066, PMID:22237022, PMID:24047651, PMID:25550361, PMID:26847029) were checked in full text: none mentions c.3870_3871insC, p.Lys1291GlnfsTer84, or residue Lys1291, so none can be cited for variant-specific PS3.
• PMID:26847029 provides gene-level evidence that BCOR loss of function (mouse Bcor exons 9-10 deletion generating a frameshift/premature stop codon, and siRNA knockdown in HL60/NB4) enhances myeloid proliferation and impairs differentiation; mechanism-level support for BCOR as a tumor suppressor, not an assay of this variant.
• PMID:22012066 shows substantially decreased BCOR mRNA and absent full-length BCOR protein in AML patients carrying other disruptive BCOR mutations (Thr733AlafsX5, Asn1485LysfsX5, Leu245ThrfsX19, Pro1115ThrfsX41, His674MetfsX41); class-level truncation evidence, not this variant.
• OncoKB variant-specific record for K1291Qfs*84 labels biological effect 'Likely Loss-of-function' and oncogenicity 'Likely Oncogenic'; this is a curated inference from the truncating consequence, not a validated functional assay, and final classifications from other sources are not used to infer criteria.
• SpliceAI (max delta score 0.074) is an in silico splice prediction only and does not constitute a functional study for PS3.

Still missing

• No variant-specific functional assay for c.3870_3871insC / p.Lys1291GlnfsTer84 exists in the evidence bundle (e.g., BCOR transcriptional repression activity, protein stability/expression, PRC1.1 complex interaction, or myeloid proliferation/differentiation readout). All retrieved BCOR functional literature is gene/class-level and does not mention this variant.

Sources

Reasoning

Governing framework is generic ACMG/AMP 2015 (Richards et al., PMID 25741868) because no ClinGen CSPEC or VCEP specification exists for BCOR (cspec found=false; final_classification_framework fallback=generic_acmg). PM3 requires a recessive-disease context and detection of the variant in trans with a pathogenic variant. The case bundle contains no proband genotype data beyond the index variant, no second BCOR allele, and no phase information; ClinVar has no submission for NM_017745.5:c.3870_3871insC. The gene context indicates BCOR germline phenotypes (oculofaciocardiodental syndrome, Lenz microphthalmia) are X-linked dominant, so no recessive/biallelic disease premise for PM3 is established, and the available variant-specific context is predominantly somatic (OncoKB: Likely Oncogenic, Likely Loss-of-function). Evidence is insufficient to apply or refute PM3; not assessed pending allelic data.

Rule

PM3 (Richards et al. 2015, PMID 25741868): For recessive disorders, detected in trans with a pathogenic variant. Generic ACMG/AMP 2015 definition applies because no BCOR CSPEC/VCEP exists.

Evidence considered

• Governing framework is generic ACMG/AMP 2015 (Richards et al., PMID 25741868); no ClinGen CSPEC or VCEP specification exists for BCOR (cspec found=false; vcep_materials.final_classification_framework.found=false, source=generic_acmg_fallback), so the standard PM3 definition applies.
• ClinVar contains no submission for NM_017745.5:c.3870_3871insC (variation_ids empty; search_status no_result), so no clinical observation of this variant - and therefore no allelic-phase observation - is available.
• pvs1_gene_context.json documents a germline disease context for BCOR with loss-of-function mechanism supported, but its inheritance list is empty; case gene context (output/gene_context_BCOR.json) notes BCOR germline mutations cause oculofaciocardiodental and Lenz microphthalmia syndromes, which are X-linked dominant phenotypes - no recessive-disease premise for PM3 is established.
• The only variant-specific functional context in the bundle is somatic (OncoKB: Likely Oncogenic, biological effect Likely Loss-of-function), which provides no germline allelic observations.
• All five retrieved full-text publications (somatic AML/MDS/retinoblastoma studies) were screened for c.3870_3871insC and p.(Lys1291GlnfsTer84); none mention this variant, so none provide affected-proband or phase evidence for PM3.

Still missing

• No proband sequencing/genotype data showing presence or absence of a second BCOR allele
• No phase information (trans/cis) for any second BCOR variant (no parental or family testing data in the bundle)
• No evidence establishing a recessive or biallelic disease context for BCOR (known germline phenotypes are X-linked dominant)
• No affected-proband allelic observations (e.g., compound heterozygosity, hemizygosity with a second somatic hit) documented in the case bundle

Sources

Reasoning

PM6 requires a de novo occurrence in a proband with the disease when maternity and paternity have not been confirmed. As with PS2, the case bundle contains no proband-level or parental testing data whatsoever, and the variant is absent from ClinVar. No source reports a de novo occurrence of c.3870_3871insC, confirmed or unconfirmed. PM6 therefore cannot be assessed under the generic ACMG/AMP 2015 framework.

Rule

PM6 (ACMG/AMP 2015, Richards et al. PMID 25741868): De novo occurrence in a proband with the disease and no family history, maternity and paternity not confirmed.

Evidence considered

• ClinVar reports no entry for this variant (case_summary evidence sentence: 'This variant is absent from ClinVar.'), so no unconfirmed de novo observations are retrievable.
• Full-text search of the 5 available publications (PMID 22012066, 22237022, 24047651, 25550361, 26847029) found no de novo/parental/mosaic occurrence data for this variant; all are somatic cancer and functional studies.
• No proband or pedigree data are present in review_manifest.json, case_summary.json, prefetch.json, evidence.json, or vcep_materials.json.

Still missing

• No de novo occurrence of this variant in any proband is reported in any source (ClinVar, literature, or case data).
• No parental testing data exist to establish or exclude de novo origin (even without formal parentage confirmation).
• No proband phenotype consistent with a BCOR germline disorder (e.g., oculofaciocardiodental/Lenz microphthalmia) is described in the bundle.

Sources

Reasoning

PP1 requires co-segregation of the variant with disease in affected family members (with the number of informative meioses/affected relatives determining strength). No segregation data exist in the case bundle: there is no family history, no affected relatives genotyped, and no segregation analysis in any available publication. The five available papers are somatic cancer cohort/functional studies with no familial segregation of this variant. Under generic ACMG/AMP 2015, PP1 cannot be applied without any meiotic segregation observations.

Rule

PP1 (ACMG/AMP 2015, Richards et al. PMID 25741868): Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease; strength scales with number of informative meioses.

Evidence considered

• Full-text search of all 5 available publications for segregation/family/pedigree terms returned zero matches; none report familial co-segregation of BCOR c.3870_3871insC.
• literature_pass.json screened no paper under a segregation/case-observation theme (criteria_index empty), and no family/pedigree data exist in the case bundle files.
• ClinVar contains no entry for this variant, so no ClinVar-curated segregation evidence is available.

Still missing

• No affected family members tested for the variant; zero informative meioses available.
• No family-based segregation study or pedigree data mentioning this variant in any source.
• No ClinVar submissions describing familial segregation for this variant.

Sources

Reasoning

PP4 requires a phenotype or family history that is highly specific for a gene with a single genetic etiology (Richards et al. 2015, PMID 25741868). The case bundle contains no proband phenotype, clinical history, or family history information (case_summary.json contains no clinical phenotype record), so phenotype specificity for this variant cannot be evaluated. PP4 is not assessable from the available evidence.

Rule

PP4: Phenotype or family history highly specific for a gene with a single genetic etiology (Richards et al. 2015, PMID 25741868)

Evidence considered

• Reviewed the consolidated case-evidence bundle (case_summary.json, evidence.json, literature_pass.json) for any proband phenotype, clinical indication, or family history description; none is present, so PP4 cannot be assessed.
• Generic ACMG/AMP 2015 (Richards et al., PMID 25741868) governs this case (no ClinGen CSPEC/VCEP exists for BCOR).

Still missing

• No proband phenotype, clinical history, or family history data available in the case bundle

Sources

Reasoning

BS3 (Richards et al. 2015, ACMG/AMP, PMID:25741868) requires well-established functional studies demonstrating no damaging effect of the variant. No functional study of NM_017745.5:c.3870_3871insC (p.Lys1291GlnfsTer84) showing a benign/neutral effect exists in the evidence bundle; the variant is a frameshift insertion in exon 9 predicting C-terminal truncation (1374 vs 1722 amino acids), and none of the retrieved full-text papers assays this allele. SpliceAI predicts no significant splicing impact (max delta 0.074), but that is an in silico prediction addressing splicing only, not a functional study, and cannot substitute for BS3. BS3 is therefore not assessable from available evidence; the gap is absence of any functional assay demonstrating lack of damaging effect for this exact variant.

Rule

generic_acmg_2015_bs3

Evidence considered

• BS3 under generic ACMG/AMP 2015 (PMID:25741868) requires well-established functional studies showing no damaging effect; no such study of c.3870_3871insC was retrieved.
• The variant is a frameshift insertion predicting C-terminal truncation p.Lys1291GlnfsTer84 (NP_060215.4, 1374 vs 1722 aa); no assay of this allele (protein stability, repressor activity, PRC1.1 interaction, proliferation/differentiation) was identified.
• SpliceAI max delta score 0.074 predicts no significant splice impact, but this in silico prediction addresses splicing only and cannot constitute well-established functional evidence of no damaging effect (BS3).
• None of the five retrieved functional-theme papers (PMID:22012066, PMID:22237022, PMID:24047651, PMID:25550361, PMID:26847029) mentions this variant, so none provides benign functional evidence for it.

Still missing

• No functional evidence demonstrating absence of a damaging effect for c.3870_3871insC (e.g., protein stability, transcriptional repressor activity, PRC1.1 complex interaction, or cellular assay). Only in silico SpliceAI (max delta 0.074) is available, which is not a functional study.

Sources

Reasoning

BS4 requires lack of segregation in affected family members (e.g., variant present in an unaffected member or absent in an affected member), which would argue against pathogenicity. No family or segregation data of any kind are available for this variant: no genotyped relatives, no pedigree, and no such observations in the available literature or ClinVar. BS4 cannot be assessed in the absence of any familial observations.

Rule

BS4 (ACMG/AMP 2015, Richards et al. PMID 25741868): Lack of segregation in affected family members (variant observed in an unaffected family member and/or absent in an affected family member).

Evidence considered

• No family/pedigree data appear anywhere in the case bundle (review_manifest, case_summary, prefetch, evidence, vcep_materials).
• Full-text search of the 5 available publications found no affected/unaffected family member genotype data relevant to this variant.
• ClinVar has no entry for this variant, so no non-segregation observations are retrievable.

Still missing

• No genotyped unaffected or affected family members exist in any source, so non-segregation cannot be evaluated.
• No familial case reports or pedigree data for this variant are available.
• Variant absent from ClinVar, precluding retrieval of any ClinVar-curated non-segregation observations.

Sources

Reasoning

Governing framework is generic ACMG/AMP 2015 (Richards et al., PMID 25741868) because no ClinGen CSPEC or VCEP specification exists for BCOR. BP2 requires observing the variant in trans with a pathogenic variant for a fully dominant disease/mechanism, or in cis with a pathogenic variant in any inheritance pattern. No second BCOR variant is observed anywhere in the case bundle (ClinVar absent; COSMIC absent; no proband sequencing data), and no phase information exists from parental/family testing. Evidence is insufficient to apply or refute BP2; not assessed pending cis/trans observation data.

Rule

BP2 (Richards et al. 2015, PMID 25741868): Observed in trans with a pathogenic variant for a fully dominant disease/mechanism, or observed in cis with a pathogenic variant in any inheritance pattern. Generic ACMG/AMP 2015 definition applies because no BCOR CSPEC/VCEP exists.

Evidence considered

• Governing framework is generic ACMG/AMP 2015 (Richards et al., PMID 25741868); no ClinGen CSPEC or VCEP specification exists for BCOR, so the standard BP2 definition applies.
• ClinVar contains no submission for NM_017745.5:c.3870_3871insC (variation_ids empty), and no second BCOR variant or cis/trans configuration is reported anywhere in the case bundle.
• No parental, familial, or phasing data are present in review_manifest.json, case_summary.json, prefetch.json, or evidence.json - the cis/trans observation required for BP2 does not exist in this case.
• All five retrieved full-text publications (somatic AML/MDS/retinoblastoma studies) were screened for c.3870_3871insC and p.(Lys1291GlnfsTer84); none mention this variant, so none provide cis/trans observations relevant to BP2.

Still missing

• No observation of a second BCOR variant in cis or in trans with this variant
• No phase data (parental testing, family segregation, or long-read/linked-read phasing) present in the case bundle
• No proband or family sequencing data to establish the cis/trans configuration of any second variant

Sources

Reasoning

BP5 requires that an alternative molecular basis for the disease be identified in the proband (Richards et al. 2015, PMID 25741868). The case bundle contains no proband-level genetic or clinical workup (no second variant, no copy-number/structural finding, no alternative diagnosis), so an alternative molecular cause can neither be confirmed nor excluded. BP5 is not assessable from the available evidence.

Rule

BP5: Alternative molecular basis for disease identified in the proband (Richards et al. 2015, PMID 25741868)

Evidence considered

• Reviewed the consolidated case-evidence bundle for any proband-level evidence of an alternative molecular diagnosis (e.g., another pathogenic variant, chromosomal abnormality, or alternate explanation); none is present, so BP5 cannot be assessed.
• Generic ACMG/AMP 2015 (Richards et al., PMID 25741868) governs this case (no ClinGen CSPEC/VCEP exists for BCOR).

Still missing

• No proband-level data to determine whether an alternative molecular basis for disease exists

Sources