Variant classification summary

NM_001123385.1:c.1005dupC

BCOR · NP_001116857.1:p.(Ser336LeufsTer45) · NM_001123385.1

GRCh37: chrX:39933593 A>AG · GRCh38: chrX:40074340 A>AG

Gene: BCOR Transcript: NM_001123385.1

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

BCOR

Transcript

NM_001123385.1

Protein

NP_001116857.1:p.(Ser336LeufsTer45)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001123385.1:c.1005dupC (p.Ser336LeufsTer45) is a frameshift duplication in BCOR exon 4 predicted to undergo nonsense-mediated decay, meeting PVS1 at very strong strength under the ClinGen SVI PVS1 framework (PMC6185798). BCOR loss-of-function is an established germline disease mechanism associated with oculofaciocardiodental (OFCD) syndrome and hereditary hematopoietic malignancy predisposition.

2

The variant is absent from all large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.

3

The variant is absent from ClinVar with no submissions from clinical laboratories. It has been observed in somatic cancers (COSMIC, n=6) consistent with a tumor suppressor role, but no germline proband observations are currently documented in the literature or databases.

4

Five publications (PMID:22012066, 22237022, 24047651, 25550361, 26847029) were reviewed and found to discuss BCOR mutations in somatic myeloid malignancies and retinoblastoma but none specifically mention NM_001123385.1:c.1005dupC. No variant-specific functional, segregation, or case-level evidence was identified for this variant.

5

Applying generic ACMG/AMP 2015 final classification combination rules: PVS1 (very strong) + PM2 (supporting) supports a classification of Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	NM_001123385.1:c.1005dupC is a frameshift duplication in exon 4 of BCOR, producing a premature termination codon at NP_001116857.1:p.(Ser336LeufsTer45) that is predicted to trigger nonsense-mediated decay (NMD). BCOR loss-of-function is an established germline disease mechanism supported by literature linking germline BCOR mutations to oculofaciocardiodental (OFCD) syndrome and hereditary hematopoietic malignancies. Under the ClinGen SVI PVS1 framework (PMC6185798), this frameshift variant meets PVS1 at very strong strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 requires a different nucleotide change at the same codon producing the same amino acid change. This is a frameshift duplication, not a nucleotide substitution at a codon producing the same missense consequence.
PS2	Not met	De novo occurrence with confirmed maternity and paternity has not been reported for NM_001123385.1:c.1005dupC in any reviewed publication or database. Exploratory literature search found no publications documenting de novo status for this exact variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies have specifically examined NM_001123385.1:c.1005dupC. Five publications (PMID:22012066, 22237022, 24047651, 25550361, 26847029) discuss BCOR mutations broadly in somatic myeloid malignancies and retinoblastoma, but none mention this exact variant. OncoKB provides gene-level annotation of BCOR loss-of-function as oncogenic, but this does not substitute for variant-specific functional evidence required for PS3.
PS4	Not met	The prevalence of this variant in affected individuals has not been established. The variant is absent from ClinVar and no cohort studies or case reports document its occurrence in individuals with BCOR-related disease. PS4 requires significantly increased prevalence in affected individuals compared to controls; without any affected observations this cannot be met.	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	PS5 requires a different pathogenic variant at the same residue identified in a recessive disorder. BCOR-associated disease is X-linked dominant (OFCD syndrome), not recessive. Additionally, this is a frameshift variant assessed under PVS1, not a missense variant with a comparator at the same residue.
PM1	Not met	This variant does not lie within a statistically significant mutational hotspot or well-established critical functional domain. Cancer Hotspots analysis confirms the residue is not significant. While BCOR contains functionally important domains (BCL6-binding domain, PUFD domain), no domain-specific enrichment is documented for this specific residue position.
PM2	Met	NM_001123385.1:c.1005dupC is absent from large population databases including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0. Under generic ACMG/AMP rules, absence from population databases (<0.1% allele frequency) supports PM2 at supporting strength.	gnomad_v2 gnomad_v4
PM4	N/A	PM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants that alter protein length without a frameshift. NM_001123385.1:c.1005dupC is an out-of-frame duplication causing a frameshift and premature termination codon; this mechanism is assessed under PVS1, not PM4.
PM5	N/A	PM5 applies when a novel missense variant occurs at the same amino acid residue as a previously established pathogenic missense variant. This is a frameshift variant producing a premature termination codon, not a missense change. PM5 candidates review confirmed no applicable same-residue comparator can be identified.	pm5_candidates
PM6	Not met	Assumed de novo occurrence (without confirmation of maternity and paternity) has not been reported for this variant. Exploratory literature search found no publication describing this variant in a patient with no family history where de novo status was presumed but unconfirmed.
PP1	Not met	Cosegregation with disease in multiple affected family members has not been demonstrated for this variant. No family studies or segregation analyses involving NM_001123385.1:c.1005dupC were identified in the reviewed literature or databases.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. NM_001123385.1:c.1005dupC is a frameshift (truncating) variant, not a missense variant. The primary disease mechanism for BCOR is loss-of-function via truncating variants.
PP3	Not met	Multiple lines of computational evidence supporting a deleterious effect are not available for this variant. REVEL and BayesDel scores are not applicable (variant is not an SNV). SpliceAI predicts no cryptic splice impact (max delta score = 0.00). HCI Prior is not available for BCOR. The frameshift nature itself predicts a damaging effect, but this evidence is already captured by PVS1 and cannot be double-counted as PP3.	spliceai
PP4	Not met	No patient-specific phenotype data are available for this variant. PP4 requires the variant to be observed in a patient whose phenotype or family history is highly specific for a disease with a single genetic etiology. Without any reported proband observations, this criterion cannot be assessed.
PP5	Not met	No reputable source has independently reported this variant as pathogenic. The variant is absent from ClinVar with no submissions from any clinical laboratory. PP5 requires a reputable source (e.g., clinical diagnostic laboratory with strong quality metrics) to have previously classified this variant as pathogenic.	clinvar
BA1	Not met	Allele frequency does not exceed the BA1 threshold of >1% in any population database. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0%). Under generic ACMG/AMP rules, BA1 requires an allele frequency >1% in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency does not exceed the BS1 threshold of >0.3%. The variant is absent from all queried population databases (gnomAD v2.1, v4.1, gnomAD-Canada). BS1 requires observation at an allele frequency too high for a rare disease variant.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation of the variant in a healthy adult individual for a fully penetrant disorder expected to manifest at an early age. The variant is absent from gnomAD, so no healthy adult carriers are documented. BS2 cannot be applied absent carrier observations.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this specific variant. The five reviewed publications (PMID:22012066, 22237022, 24047651, 25550361, 26847029) discuss BCOR mutations in somatic cancer contexts but none specifically study NM_001123385.1:c.1005dupC. BS3 requires variant-specific functional evidence showing no deleterious effect, which is not available.
BS4	Not met	No evidence of non-segregation with disease in affected family members has been identified. BS4 requires observation that the variant does not segregate with the disease phenotype in affected families. No family studies involving this variant were found in the literature or exploratory search.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary known mechanism of disease. NM_001123385.1:c.1005dupC is itself a truncating (frameshift) variant, not a missense variant. BP1 is designed to downgrade missense variants when the gene's disease mechanism is primarily truncating.
BP2	Not met	No evidence documents this variant observed in trans with a pathogenic BCOR variant or in cis with a pathogenic variant in any individual. BCOR is located on the X chromosome and associated disorders follow X-linked dominant inheritance, making trans observations unlikely. No published reports of co-occurrence with other BCOR pathogenic variants were identified.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. NM_001123385.1:c.1005dupC is an out-of-frame duplication causing a frameshift, not an in-frame event. BP3 is designed for variants that alter protein length without disrupting the reading frame.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. NM_001123385.1:c.1005dupC is a frameshift variant producing a premature termination codon predicted to result in a severely truncated protein (p.Ser336LeufsTer45, truncating 1420 amino acids). While SpliceAI shows no cryptic splice impact (max delta = 0.00), this does not constitute evidence of a benign effect — the variant is clearly protein-damaging by its frameshift mechanism. REVEL and BayesDel are not applicable to frameshifts.	spliceai
BP5	Not met	BP5 requires observation of the variant in a case with an alternate molecular basis for disease. No case has been reported carrying this variant alongside an alternate confirmed molecular diagnosis. BP5 cannot be applied in the absence of any case-level data.
BP6	Not met	No reputable source has reported this variant as benign or likely benign. The variant is absent from ClinVar with no benign classifications from any submitter. BP6 requires a reputable source (e.g., clinical diagnostic laboratory) to have previously classified this variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence and the nucleotide is not highly conserved. NM_001123385.1:c.1005dupC is a frameshift duplication, not a synonymous variant.

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