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.1 The variant is absent from all large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.2 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.3 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. Applying generic ACMG/AMP 2015 final classification combination rules: PVS1 (very strong) + PM2 (supporting) supports a classification of Likely Pathogenic.4
BCOR
Final classification
VUS
BCOR c.1005dup · p.Ser336LeufsTer45
BCOR
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to VUS.
Classification rationale
PVS1PM2
VUS
BCOR c.1005dup
PVS1 + PM2
→
VUS
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
4
generic_acmg_combination_rules
Gene diagram
· NM_001123385.1 · variants mapped to exon structure
BCOR
NM_001123385.1
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
review
Pathogenic
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.
Frameshift variant in exon 4/15 creating a premature termination codon at Ser336 (of 1756 amino acids)predicted to undergo NMDBCOR loss-of-function is an established germline disease mechanism (OFCD syndrome
✓
PM2
supporting
Pathogenic
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 v2.1: absent (0 alleles in 0 chromosomes queriedvariant not present in dataset)gnomAD v4.1: absent (0 alleles
Assessed · not applied
Pathogenic
PS2
De novo occurrence with confirmed maternity and paternity has not been reported for NM_001123385.1:c.1005dupC in any reviewed publication or database.
PS3
No well-established in vitro or in vivo functional studies have specifically examined NM_001123385.1:c.1005dupC.
PS4
The prevalence of this variant in affected individuals has not been established.
PM1
This variant does not lie within a statistically significant mutational hotspot or well-established critical functional domain.
PM6
Assumed de novo occurrence (without confirmation of maternity and paternity) has not been reported for this variant.
PP1
Cosegregation with disease in multiple affected family members has not been demonstrated for this variant.
PP3
Multiple lines of computational evidence supporting a deleterious effect are not available for this variant.
PP4
No patient-specific phenotype data are available for this variant.
PP5
No reputable source has independently reported this variant as pathogenic.
Benign
BA1
Allele frequency does not exceed the BA1 threshold of >1% in any population database.
BS1
Allele frequency does not exceed the BS1 threshold of >0.3%.
BS2
BS2 requires observation of the variant in a healthy adult individual for a fully penetrant disorder expected to manifest at an early age.
BS3
No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this specific variant.
BS4
No evidence of non-segregation with disease in affected family members has been identified.
BP2
No evidence documents this variant observed in trans with a pathogenic BCOR variant or in cis with a pathogenic variant in any individual.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product.
BP5
BP5 requires observation of the variant in a case with an alternate molecular basis for disease.
BP6
No reputable source has reported this variant as benign or likely benign.
N/A · 7
PS1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV60706968, n = 6 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
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