About BCOR
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BCOR c.1005dup, p.(Ser336LeufsTer45)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
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.
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
6 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV60706968, n = 6 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 17 not met · 1 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
The variant is absent from all large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.
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.
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.
No criteria match.
Met · 2
PVS1 Very strongNM_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. Details ▾Hide ▴
Evidence considered
- Frameshift variant in exon 4/15 creating a premature termination codon at Ser336 (of 1756 amino acids)
- predicted to undergo NMD
- BCOR loss-of-function is an established germline disease mechanism (OFCD syndrome
- germline predisposition to myeloid malignancies)
- ClinGen SVI PVS1 generic framework (PMC6185798) supports PVS1 at default strength for frameshift variants in genes with established LOF mechanism
Still missing
- A more recent transcript version NM_001123385.2 is available
- confirm PVS1 applicability on the most current transcript
- Confirm that exon 4 is present in all biologically relevant BCOR transcripts per PMC6185798 criteria
Sources
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (0 alleles in 0 chromosomes queried
- variant not present in dataset)
- gnomAD v4.1: absent (0 alleles
- gnomAD-Canada v1.0: absent (AC=0
- AN=0
- AF=0.0)
Sources
Not met · 17 · evaluated, threshold not reached
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. Exploratory literature search found no publications documenting de novo status for this exact variant. Details ▾Hide ▴
Evidence considered
- Exploratory search of PubMed and ClinVar found no de novo reports for this variant
Still missing
- No published case reports or family studies identifying this variant as de novo
PS4 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. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar (no submissions from any laboratory)
- Absent from gnomAD v2.1 and v4.1 (no population allele frequency data)
- No publication reporting this variant in affected probands
Still missing
- No affected proband counts available
- PS4 cannot be applied without case-level observation data
- Clinical laboratories may hold unpublished observations of this variant
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not statistically significant
- No domain-specific PM1 framework available for BCOR under generic ACMG
Still missing
- No established BCOR domain map for germline PM1 application
PM6 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. Details ▾Hide ▴
Evidence considered
- No publication reports this variant as assumed de novo
Still missing
- No sporadic case reports available for this variant
PP1 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. Details ▾Hide ▴
Evidence considered
- No cosegregation data found in PubMed or ClinVar
Still missing
- No family-based segregation studies available for this variant
PP3 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: no splice impact (max delta = 0.00
- donor gain = 0.00
- acceptor gain = 0.00)
- REVEL: not applicable (non-SNV)
- BayesDel: not applicable (non-SNV)
- HCI Prior: not available for BCOR
Still missing
- No in silico tools validated for scoring frameshift variants
Sources
PP4 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. Details ▾Hide ▴
Still missing
- No proband phenotype data available
- clinical testing laboratories may hold unpublished case-level information
PP5 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. Details ▾Hide ▴
Evidence considered
- ClinVar: no entry for this variant (0 submissions
- 0 classifications)
Still missing
- No external classification available to support PP5
Sources
BA1 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF = 0%)
- gnomAD v4.1: absent (AF = 0%)
- gnomAD-Canada v1.0: absent (AF = 0.0)
Sources
BS1 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF = 0%)
- gnomAD v4.1: absent (AF = 0%)
Sources
BS2 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. Details ▾Hide ▴
Evidence considered
- No healthy adult carriers identified in gnomAD or literature
Still missing
- No population carrier data available to support or refute BS2
BS3 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. Details ▾Hide ▴
Evidence considered
- No variant-specific functional studies identified showing benign effect
- Five publications reviewed: none contain functional data on c.1005dupC
Still missing
- No functional data available for this variant to assess BS3
Sources
2201206622237022240476512555036126847029
BS4 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. Details ▾Hide ▴
Evidence considered
- No family segregation studies available for this variant
Still missing
- No family-based evidence to support or refute BS4
BP2 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. Details ▾Hide ▴
Evidence considered
- BCOR is X-linked
- observation in trans with another BCOR pathogenic variant is unlikely
- No reports of compound heterozygosity or double mutants involving this variant
Still missing
- No co-occurrence data available
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 (no cryptic splice effect)
- REVEL/BayesDel: not applicable (non-SNV)
Sources
BP5 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. Details ▾Hide ▴
Still missing
- No case observations available to assess BP5
BP6 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. Details ▾Hide ▴
Not assessed · 1 · no assessment recorded
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB curated annotation: BCOR loss-of-function variants classified as Likely Oncogenic
- COSMIC COSV60706968: observed in somatic cancers (n=6)
- supporting gene-level tumor suppressor role
Still missing
- No variant-specific functional assay data (e.g.
- Western blot
- mRNA expression
- reporter assays) for c.1005dupC
- While BCOR LOF is well-studied in somatic contexts
- dedicated germline functional studies for this variant are absent
Sources
2201206622237022240476512555036126847029
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 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. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 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. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 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. Details ▾Hide ▴
Evidence considered
- Variant is frameshift
- not missense
- classic PM5 semantics do not apply
- No same-residue comparator variants identified in ClinVar
Sources
pm5_candidates
PP2 N/APP2 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. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 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. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 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. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 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. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 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. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- BCOR
- Transcript
- NM_001123385.1
- Coding (HGVS c.)
- NM_001123385.1:c.1005dup
- Protein (HGVS p.)
- NP_001116857.1:p.(Ser336LeufsTer45)
- GRCh38
- chrX:40074340 A>AG
- GRCh37
- chrX:39933593 A>AG
- COSMIC
- COSV60706968
Gene diagram
Every interpreted variant in BCOR, mapped onto the exon structure of NM_001123385.1. Select a row to find it on the plot.
BCORNM_001123385.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BCOR
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: no splice impact (max delta = 0.00
- donor gain = 0.00
- acceptor gain = 0.00)
- REVEL: not applicable (non-SNV)
- BayesDel: not applicable (non-SNV)
- HCI Prior: not available for BCOR
Still missing
- No in silico tools validated for scoring frameshift variants
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 (no cryptic splice effect)
- REVEL/BayesDel: not applicable (non-SNV)
Sources
BP7 N/ABP7 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. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 22012066 ↗Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype.No paper-specific finding is recorded.
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PMID 22237022 ↗A novel retinoblastoma therapy from genomic and epigenetic analyses.No paper-specific finding is recorded.
-
PMID 24047651 ↗BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders.No paper-specific finding is recorded.
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PMID 25550361 ↗Acute myeloid leukemia ontogeny is defined by distinct somatic mutations.No paper-specific finding is recorded.
-
PMID 26847029 ↗BCOR regulates myeloid cell proliferation and differentiation.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001123385.1%3Ac.1005dupC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/X-39933593-A-AG?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chrX-40074340-A-AG?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001123385.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/BCOR/S336Lfs*45
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=139455535
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV60706968, n = 6 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.