NM_004656.4:c.1081_1084del (p.Leu361ThrfsTer68) is a frameshift deletion in exon 11 of BAP1, predicted to cause nonsense-mediated decay and loss of protein function. BAP1 loss of function is an established mechanism for BAP1 tumor predisposition syndrome.1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting its rarity in the general population.2 This variant is absent from ClinVar and has not been previously reported in the literature with variant-specific evidence.3 SpliceAI predicts no significant splicing impact (max delta 0.09), and in silico missense predictors are not applicable to this deletion variant.4 No variant-specific functional studies, segregation data, or de novo observations were identified. Two BAP1-focused publications (PMID:18757409, PMID:21874000) were reviewed in full text; neither mentions NM_004656.4:c.1081_1084delCTAG.5
BAP1
Final classification
Likely Pathogenic
BAP1 c.1081_1084del · p.Leu361ThrfsTer68
BAP1
NM_004656.4:c.1081_1084del (p.Leu361ThrfsTer68) is a frameshift deletion in exon 11 of BAP1, predicted to cause nonsense-mediated decay and loss of protein function. BAP1 loss of function is an established mechanism for BAP1 tumor predisposition syndrome.
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 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
BAP1 c.1081_1084del
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
Gene diagram
· NM_004656.4 · variants mapped to exon structure
BAP1
NM_004656.4
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 · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
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 = 0.09).
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment
18757409 ↗
BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.
ONCOKB