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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
Population frequency
“
Absent from gnomAD v4.1.
“
Absent from gnomAD v2.1.
“
This variant is absent from gnomAD-Canada.
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.
Literature · 5 PMIDs triaged · 5 high-priority
5papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
22012066 ↗
functional
Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype.
Among acute myeloid leukemia (AML) patients with a normal karyotype (CN-AML), NPM1 and CEBPA mutations define World Health Organization 2008 provisional entities accounting for approximately 60% of patients, but the remaining 40% are molecularly poorly characterized. Using whole-exome sequencing of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3-ITD, IDH1, and MLL-PTD, we newly identifie
BS3PM1PS3
22237022 ↗
functional
A novel retinoblastoma therapy from genomic and epigenetic analyses.
Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss
BS3PM1PS3
24047651 ↗
functional
BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders.
Patients with low-risk myelodysplastic syndromes (MDS) that rapidly progress to acute myeloid leukemia (AML) remain a challenge in disease management. Using whole-exome sequencing of an MDS patient, we identified a somatic mutation in the BCOR gene also mutated in AML. Sequencing of BCOR and related BCORL1 genes in a cohort of 354 MDS patients identified 4.2% and 0.8% of mutations respectively. BC
BS3PM1PS3
25550361 ↗
functional
Acute myeloid leukemia ontogeny is defined by distinct somatic mutations.
Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defin
BS3PM1PS3
26847029 ↗
functional
BCOR regulates myeloid cell proliferation and differentiation.
BCOR is a component of a variant Polycomb group repressive complex 1 (PRC1). Recently, we and others reported recurrent somatic BCOR loss-of-function mutations in myelodysplastic syndrome and acute myelogenous leukemia (AML). However, the role of BCOR in normal hematopoiesis is largely unknown. Here, we explored the function of BCOR in myeloid cells using myeloid murine models with Bcor conditiona
BS3PM1PS3
Sources & reference links