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BCOR
Final classification
Likely Pathogenic
PVS1PM2BP4
BCOR
c.2265C>A
p.Tyr755Ter
nonsense · exon 4
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's established disease mechanism is loss of function: germline mutations cause oculofaciocardiodental and Lenz microphthalmia syndromes, and truncating mutations are found in retinoblastoma, AML, and MDS. This nonsense variant (p.Tyr755Ter), predicted to undergo nonsense-mediated decay, produces a non-functional BCOR protein, precisely the loss-of-function mechanism linked to BCOR-related disease.

Transcript
NM_017745.5
HGVS · transcript:coding
NM_017745.5:c.2265C>A
GRCh38
chrX:40073081 G>T
GRCh37
chrX:39932334 G>T
Basis Likely Pathogenic: PVS1 (Very Strong) + PM2 (Supporting) satisfies the ClinGen SVI PVS1-plus-one-supporting combination rule; the lone BP4 does not conflict. ▾
Likely Pathogenic: PVS1 (Very Strong) + PM2 (Supporting) satisfies the ClinGen SVI PVS1-plus-one-supporting combination rule; the lone BP4 does not conflict.
Classification rationale
PVS1PM2 BP4 Likely Pathogenic
BCOR c.2265C>A nonsense · exon 4

PVS1 (Very Strong): nonsense p.Tyr755Ter predicted to trigger nonsense-mediated decay, truncating the 1722-aa BCOR protein. PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. BP4 (Supporting): SpliceAI max delta 0.00 predicts no splicing disruption. Synthesis: Likely Pathogenic, per the ClinGen SVI rule that PVS1 (Very Strong) plus one supporting pathogenic criterion (PM2) yields Likely Pathogenic; BP4 does not reach a benign threshold.

PVS1 + PM2 + BP4 → Likely Pathogenic
Gene diagram · NM_017745.5 · variants mapped to exon structure
BCOR NM_017745.5
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 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 review Pathogenic
Met (Very Strong): nonsense p.Tyr755Ter truncates the 1722-aa protein, with the premature stop >50 nt upstream of the last exon-exon junction, predicting nonsense-mediated decay.
pvs1_variant_assessment.json classifies NM_017745.5:c.2265C>A as consequence_class='nonsense', variant_bucket='nonsense', and recommends the generic PVS1 framework (PMC6185798) with suggested_default_strength='PVS1', subject to confirming NMD prediction and exon importance.prefetch.json exon/CDS coordinate map (selector_short) shows the exon containing c.2265 spans c.166-c.2997, while the terminal exon spans c.4875-*863 (3'UTR); the resulting PTC at c.2265 (p.Tyr755Ter) is far more than 50 nt from the final exon-exon junction, satisfying the ClinGen SVI criterion for NMD-predicted transcripts.prefetch.json predicted reference protein length is 1722 amino acids (position_last_original=1722), confirming the p.Tyr755Ter truncation removes the majority of the protein, consistent with a damaging LOF outcome if NMD were to be escaped.
pvs1_generic_framework ↗oncokb ↗gnomad_v2 ↗
✓
PM2 supporting Pathogenic
Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, with no reported homozygotes or hemizygotes.
gnomAD v2.1 reports the variant as absent.gnomAD v4.1 reports the variant as absent.gnomAD-Canada v1.0 reports the variant as absent.
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
✓
BP4 supporting Benign
Met (Supporting): SpliceAI max delta 0.00 vs the >=0.2 splice-altering threshold predicts no splicing disruption.
SpliceAI Lookup result: max_delta_score=0.00 (all four DS_AG/AL/DG/DL = 0.0) for NM_017745.5:c.2265C>A, retrieved from evidence.json/case_summary.json.Widely accepted SpliceAI threshold of delta score >=0.2 to flag a possible splice-altering effect, from Jaganathan KM et al., 'Predicting Splicing from Primary Sequence with Deep Learning', Cell 2019, PMID 30661751; the observed 0.00 score is far below this threshold, supporting no predicted splice disruption.
spliceai ↗
Assessed · not applied · 3 not met · 12 not assessed
Pathogenic
PS2 Not assessed: no parental testing or de novo evidence for this variant was available.
PS3 Not assessed: no validated functional assay of this specific variant (p.Tyr755Ter) was available.
PS4 Not assessed: no case-control or affected-case frequency data for this variant was available.
PM3 Not assessed: no second pathogenic variant or phase/inheritance information was available.
PM6 Not assessed: no de novo observation or parental genotype information for this variant was available.
PP1 Not assessed: no family pedigree or segregation data for this variant was available.
PP3 Not met: SpliceAI max delta 0.00 across all four splice categories, far below any splice-disruption threshold.
PP4 Not assessed: no patient phenotype or family history specific to a single-gene etiology was provided.
Benign
BA1 Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, with no allele frequency approaching the benign threshold.
BS1 Not met: absent from population datasets, so no allele frequency exceeds the benign-frequency threshold.
BS2 Not assessed: no documented observation of this variant in healthy adults or unaffected relatives was available.
BS3 Not assessed: no functional assay data showing a benign effect for this exact variant was available.
BS4 Not assessed: no tested unaffected relatives or non-segregation evidence was available.
BP2 Not assessed: no second variant or phase information was available to establish trans/cis configuration.
BP5 Not assessed: no competing pathogenic variant or alternative molecular diagnosis was available.
N/A · 10 PS1 · PM1 · PM4 · PM5 · PP2 · PP5 · BP1 · BP3 · BP6 · 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 = 0.00). BayesDel score = 0.66.
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 ↗
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
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
24047651 ↗ BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders. ONCOKB
25550361 ↗ Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. ONCOKB
26847029 ↗ BCOR regulates myeloid cell proliferation and differentiation. ONCOKB