NM_000059.4:c.7092_7099del (p.Glu2364AspfsTer25) is an 8 bp frameshift deletion in BRCA2 exon 14 that creates a premature termination codon, removing the DNA-binding domain (aa 2481–3186) and nuclear localization signals. It is classified as Pathogenic under ENIGMA BRCA1/2 v1.2.0.1 PVS1 (very strong) is applied: ENIGMA Table 4 assigns full PVS1 weight to protein termination codon variants in BRCA2 exon 14. The frameshift is predicted to undergo nonsense-mediated decay and eliminates all C-terminal functional domains.2 PM5_PTC (strong) is applied: ENIGMA Table 4 assigns PM5_Strong (PTC) for exon 14 based on the presence of proven pathogenic PTC variants in this exon, providing additional weight beyond PVS1.3 PM2 (supporting) is applied: the variant is absent from gnomAD v2.1 (exome, non-cancer), v4.1 (non-cancer), and gnomAD-Canada, meeting the ENIGMA PM2_Supporting threshold.4 This combination (PVS1 + PM5_PTC Strong + PM2 Supporting) satisfies the ENIGMA Table 3 rule for Pathogenic: 1 Very Strong + ≥1 Strong criterion.5
BRCA2
Final classification
Pathogenic
BRCA2 c.7092_7099del · p.Glu2364AspfsTer25
BRCA2
NM_000059.4:c.7092_7099del (p.Glu2364AspfsTer25) is an 8 bp frameshift deletion in BRCA2 exon 14 that creates a premature termination codon, removing the DNA-binding domain (aa 2481–3186) and nuclear localization signals. It is classified as Pathogenic under ENIGMA BRCA1/2 v1.2.0.
ENIGMA BRCA1/2 v1.2.0 Table 3: PVS1 (Very Strong) + PM5_PTC (Strong) satisfies the Pathogenic combination rule '1 Very Strong + >=1 Strong'. PM2 (Supporting) provides additional evidence but is not required for this classification.
Classification rationale
PVS1PM2PM5
Pathogenic
BRCA2 c.7092_7099del
PVS1 + PM2 + PM5
→
Pathogenic
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 10 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_000059.4:c.7092_7099del is an 8 bp frameshift deletion in BRCA2 exon 14 (c.7008–7435), predicted to produce a premature termination codon at p.(Glu2364AspfsTer25). Loss of function is a well-established disease mechanism for BRCA2. Under ENIGMA BRCA1/2 v1.2.0 Specifications Table 4, protein termination codon (PTC) variants in exon 14 are assigned PVS1 at very strong weight. The truncation occurs upstream of the BRCA2 DNA-binding domain (aa 2481–3186), and the variant is expected to undergo nonsense-mediated decay. No SpliceAI-predicted splicing impact (max delta = 0.01) complicates the null interpretation.
ENIGMA Table 4: BRCA2 exon 14 PTC variants receive PVS1 at very strong strengthFrameshift deletion c.7092_7099del in exon 14premature stop at p.(Glu2364AspfsTer25)
✓
PM2
supporting
Pathogenic
Under ENIGMA PM2_Supporting, the variant is absent from gnomAD v2.1 (non-cancer, exome only) and gnomAD v4.1 (non-cancer) in all outbred populations. This meets the ENIGMA threshold for PM2 at supporting strength.
Absent from gnomAD v2.1 (exomenon-cancer)Absent from gnomAD v4.1 (non-cancer)
✓
PM5
strong
Pathogenic
ENIGMA Specifications Table 4 assigns PM5_Strong (PTC) for protein termination codon variants in BRCA2 exon 14. This exon is not among the PM5_N/A exons (E6, E12, E27). A proven pathogenic PTC variant has been observed in this exon previously, justifying the additional weight beyond PVS1.
ENIGMA Table 4: BRCA2 exon 14 receives PM5_Strong (PTC)Exon 14 is in the PM5_PTC applicable set (not E6E12
Assessed · not applied
Pathogenic
PS3
No variant-specific functional assay data are available for NM_000059.4:c.7092_7099del.
PS4
No case-control study data are available for this variant.
PP1
No segregation data are available for this variant.
PP4
The variant was not found in Li et al.
Benign
BA1
ENIGMA BA1 requires the variant to have a filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only) and/or v3.1 (non-cancer).
BS1
ENIGMA BS1_Strong requires FAF > 0.0001 (0.01%), and BS1_Supporting requires FAF > 0.00002 (0.002%).
BS2
ENIGMA BS2 requires a points-based assessment of the absence of Fanconi Anemia features in individuals homozygous or compound heterozygous for the variant.
BS3
ENIGMA BS3 applies to well-established functional studies showing no damaging effect on protein function.
BS4
ENIGMA BS4 requires a quantitative cosegregation LR ≤ 0.48 showing lack of segregation with disease.
BP5
The variant was not found in Li et al.
N/A · 15
PS1 · PS2 · PM1 · PM3 · PM4 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
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 = 0.01).
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
9Sources
Triaged references · 5 PMIDs not cited in assessment
20878484 ↗
A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.
ONCOKB
24312913 ↗
A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.
ONCOKB