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NM_017745.5:c.3870_3871insC
p.Lys1291GlnfsTer84 · BCOR
ACMG/AMP
0%
complete
Final classification
Likely Pathogenic
PVS1PM2BP4
BCOR
c.3870_3871insC
p.Lys1291GlnfsTer84
frameshift · exon 9
Gene context NCBI Gene ↗ OncoKB ↗

BCOR (BCL6 co-repressor) encodes a transcriptional repressor that silences target genes by working with the BCL6 protein and histone-modifying complexes, helping maintain the correct chromatin state. It is essential for early embryonic development, normal germinal center formation in B cells, blood cell production, and mesenchymal stem cell function. Germline mutations in BCOR cause the inherited oculofaciocardiodental and Lenz microphthalmia syndromes. In cancer, BCOR acts as a tumor suppressor: gene fusions drive certain soft tissue and endometrial stromal sarcomas and acute promyelocytic leukemia, while truncating mutations are found in retinoblastoma, acute myeloid leukemia, and myelodysplastic syndrome.

This variant

BCOR is a tumor suppressor in which truncating mutations drive retinoblastoma, acute myeloid leukemia, and myelodysplastic syndrome, while germline loss of function causes oculofaciocardiodental syndrome. This frameshift truncates the C-terminal PRC1-interaction region and is predicted to trigger nonsense-mediated decay — the same loss-of-function mechanism implicated in these disorders — supporting its Likely Pathogenic classification.

Transcript
NM_017745.5
HGVS · transcript:coding
NM_017745.5:c.3870_3871insC
GRCh38
chrX:40062946 T>TG
GRCh37
chrX:39922199 T>TG
Likely Pathogenic: 1 Very Strong (PVS1) + 1 supporting (PM2) maps to Likely Pathogenic under the ClinGen SVI 2020 PM2-downgrade rule (posterior probability 0.988). The met BP4 (splice-only, supporting) was not counted as benign evidence because it does not apply to this frameshift's loss-of-function consequence.
Classification rationale
PVS1PM2 BP4 Likely Pathogenic
BCOR c.3870_3871insC frameshift · exon 9

PVS1 (Very Strong): frameshift p.(Lys1291GlnfsTer84) is predicted to trigger nonsense-mediated decay, truncating the BCOR C-terminus. PM2 (Supporting): allele frequency 0 in gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.1% threshold. BP4 (Supporting, met but not counted): SpliceAI predicts no splice impact (max delta 0.074), but this was excluded from the combination as it does not address the frameshift consequence. Overall: Likely Pathogenic — PVS1 (Very Strong) + PM2 (Supporting) per the ClinGen SVI 2020 combination rule.

PVS1 + PM2 + BP4 → Likely Pathogenic
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.
Gene diagram · NM_017745.5 · variants mapped to exon structure
BCOR NM_017745.5
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 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 · 3
Strength Supporting Moderate Strong Very strong
PVS1 very strong Pathogenic
Met (very strong): the 1-nt insertion creates frameshift p.(Lys1291GlnfsTer84) whose premature stop codon sits 753 nt upstream of the final exon-exon junction, predicted to trigger nonsense-mediated decay.
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.
pvs1_generic_framework ↗PMID:26847029 ↗PMID:24047651 ↗
PM2 supporting Pathogenic
Met (supporting): allele frequency is 0 in gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.1% threshold.
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).
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 supporting review Benign
Met (supporting): SpliceAI max delta 0.074, below the <0.1 BP4 threshold. Flagged for human review: this reflects splice prediction only and does not contradict the frameshift's loss-of-function consequence.
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.
spliceai ↗
Assessed · not applied · 7 not met · 10 not assessed
Pathogenic
PS2 Not assessed: no proband or parental testing data were available to confirm a de novo occurrence.
PS3 Not assessed: no functional assay performed on this exact variant was available.
PS4 Not met: no case-control or cohort enrichment data exist for this exact variant.
PM3 Not assessed: no second BCOR allele or phase data were available, and BCOR germline disease is X-linked dominant, not recessive.
PM6 Not assessed: no parental testing data were available to support an unconfirmed de novo occurrence.
PP1 Not assessed: no family members were genotyped, so no segregation data were available.
PP3 Not met: SpliceAI max delta 0.074, below the >0.2 splice-altering threshold.
PP4 Not assessed: no proband phenotype or family history was available to evaluate gene-specificity.
PP5 Not met: the variant is absent from ClinVar, so no expert-panel pathogenic classification exists.
Benign
BA1 Not met: allele frequency is 0 in population databases, far below the >1% BA1 threshold.
BS1 Not met: allele frequency is 0, below the >0.3% BS1 threshold.
BS2 Not met: no healthy-adult observation exists; the variant is absent from population cohorts and ClinVar.
BS3 Not assessed: no functional study showing a benign effect of this exact variant was available.
BS4 Not assessed: no family or segregation data were available.
BP2 Not assessed: no second BCOR variant or phase information was available.
BP5 Not assessed: no proband-level workup was available to confirm or exclude an alternative molecular cause.
BP6 Not met: the variant is absent from ClinVar, so no expert-panel benign classification exists.
N/A · 8 PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
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 is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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 ↗
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 3 further PMIDs triaged but not cited — see Sources & references.
Rule & framework references · cited for criterion definitions, not variant evidence
24047651 ↗ BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders.
26847029 ↗ BCOR regulates myeloid cell proliferation and differentiation.
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 3 PMIDs not cited in assessment
22012066 ↗ Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. ONCOKB
22237022 ↗ A novel retinoblastoma therapy from genomic and epigenetic analyses. ONCOKB
25550361 ↗ Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. ONCOKB