Variant classification summary

NM_017745.5:c.2265C>A

BCOR · NP_060215.4:p.(Tyr755Ter) · NM_017745.5

GRCh37: chrX:39932334 G>T · GRCh38: chrX:40073081 G>T

Gene: BCOR Transcript: NM_017745.5

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting BP4 supporting

Variant details

Gene

BCOR

Transcript

NM_017745.5

Protein

NP_060215.4:p.(Tyr755Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): nonsense p.Tyr755Ter predicted to trigger nonsense-mediated decay, truncating the 1722-aa BCOR protein.

2

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

3

BP4 (Supporting): SpliceAI max delta 0.00 predicts no splicing disruption.

4

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.

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	Met	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_generic_framework pvs1_variant_assessment pvs1_gene_context oncokb gnomad_v2 gnomad_v4
PS1	N/A	Not applicable: as a nonsense change, no altered amino acid exists to compare against a previously established pathogenic variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental testing or de novo evidence for this variant was available.
PS3	Not assessed	Not assessed: no validated functional assay of this specific variant (p.Tyr755Ter) was available.
PS4	Not assessed	Not assessed: no case-control or affected-case frequency data for this variant was available.	generic_acmg_combination_rules
PM1	N/A	Not applicable: as a nonsense change, no altered residue exists to evaluate for mutational hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, with no reported homozygotes or hemizygotes.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no second pathogenic variant or phase/inheritance information was available.
PM4	N/A	Not applicable: as a nonsense change, protein length is not altered, so there is nothing for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: as a nonsense change, no missense change exists at this residue to compare against a pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo observation or parental genotype information for this variant was available.
PP1	Not assessed	Not assessed: no family pedigree or segregation data for this variant was available.
PP2	N/A	Not applicable: as a nonsense change, no missense variant exists to evaluate against the gene's missense-constraint properties.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.00 across all four splice categories, far below any splice-disruption threshold.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype or family history specific to a single-gene etiology was provided.	generic_acmg_combination_rules
PP5	N/A	Not applicable: variant is absent from ClinVar, so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, with no allele frequency approaching the benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from population datasets, so no allele frequency exceeds the benign-frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no documented observation of this variant in healthy adults or unaffected relatives was available.
BS3	Not assessed	Not assessed: no functional assay data showing a benign effect for this exact variant was available.
BS4	Not assessed	Not assessed: no tested unaffected relatives or non-segregation evidence was available.
BP1	N/A	Not applicable: as a nonsense change, the truncating-mechanism rule for missense variants does not apply.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second variant or phase information was available to establish trans/cis configuration.
BP3	N/A	Not applicable: as a nonsense change, the variant does not alter protein length in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): SpliceAI max delta 0.00 vs the >=0.2 splice-altering threshold predicts no splicing disruption.	spliceai
BP5	Not assessed	Not assessed: no competing pathogenic variant or alternative molecular diagnosis was available.	generic_acmg_combination_rules
BP6	N/A	Not applicable: variant is absent from ClinVar, so no expert-panel benign assertion exists.	clinvar
BP7	N/A	Not applicable: as a nonsense change, the silent-variant premise does not hold.	generic_acmg_combination_rules

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