NM_017745.5:c.3870_3871insC

BCOR · NP_060215.4:p.(Lys1291GlnfsTer84) · NM_017745.5

GRCh37: chrX:39922199 T>TG · GRCh38: chrX:40062946 T>TG

Gene: BCOR Transcript: NM_017745.5

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

BCOR

Transcript

NM_017745.5

Protein

NP_060215.4:p.(Lys1291GlnfsTer84)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 likely-pathogenic rule: 1 Very Strong (PVS1) + 1 Moderate (PM2) -> Likely Pathogenic (Richards et al. 2015, PMID:25741868); with PM2 met at supporting strength per the ClinGen SVI 2020 downgrade, the addendum PVS1 + 1 supporting criterion = Likely Pathogenic (Post_P 0.988) governs, and the adjudicated splice-sub-path BP4 is not counted as benign evidence against the frameshift LoF consequence, so the combination PVS1 + PM2(supporting) yields Likely Pathogenic.

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): 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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:26847029 PMID:24047651 gnomad_v2 gnomad_v4 gnomad_canada oncokb
PS1	N/A	Not applicable: a frameshift produces no altered amino acid, so there is no change to compare with a previously established pathogenic variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband or parental testing data were available to confirm a de novo occurrence.
PS3	Not assessed	Not assessed: no functional assay performed on this exact variant was available.	generic_acmg_combination_rules
PS4	Not met	Not met: no case-control or cohort enrichment data exist for this exact variant.	generic_acmg_combination_rules clinvar oncokb
PM1	N/A	Not applicable: PM1 requires a missense variant, and a frameshift leaves no altered residue to evaluate.	generic_acmg_combination_rules
PM2	Met	Met (supporting): allele frequency is 0 in gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no second BCOR allele or phase data were available, and BCOR germline disease is X-linked dominant, not recessive.	generic_acmg_combination_rules clinvar pvs1_gene_context
PM4	N/A	Not applicable: PM4 covers in-frame length changes or stop-loss variants; a frameshift instead shifts the reading frame.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense change, which a frameshift does not produce.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no parental testing data were available to support an unconfirmed de novo occurrence.
PP1	Not assessed	Not assessed: no family members were genotyped, so no segregation data were available.
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a frameshift.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.074, below the >0.2 splice-altering threshold.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family history was available to evaluate gene-specificity.	generic_acmg_combination_rules
PP5	Not met	Not met: the variant is absent from ClinVar, so no expert-panel pathogenic classification exists.	clinvar
BA1	Not met	Not met: allele frequency is 0 in population databases, far below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: allele frequency is 0, below the >0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: no healthy-adult observation exists; the variant is absent from population cohorts and ClinVar.	gnomad_v2 gnomad_v4 gnomad_canada clinvar generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no functional study showing a benign effect of this exact variant was available.	generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no family or segregation data were available.
BP1	N/A	Not applicable: BP1 applies to missense variants, and this is a frameshift.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second BCOR variant or phase information was available.	generic_acmg_combination_rules clinvar
BP3	N/A	Not applicable: BP3 applies to in-frame changes in repetitive regions, and this is a frameshift.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	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 generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband-level workup was available to confirm or exclude an alternative molecular cause.	generic_acmg_combination_rules
BP6	Not met	Not met: the variant is absent from ClinVar, so no expert-panel benign classification exists.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants, and this frameshift alters the protein sequence.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.