NM_000059.3:c.3881T>G (p.Leu1294Ter) is a nonsense variant in BRCA2 exon 11 that introduces a premature termination codon at residue 1294 of 3418, predicted to result in loss of the C-terminal DNA-binding domain and nuclear localization signals.1 PVS1 (Very Strong) is met per ENIGMA Specifications Table 4, which assigns PVS1 to BRCA2 exon 11 PTC variants. Loss of function is the established disease mechanism for BRCA2.2 PM5_Strong (PTC) is met per ENIGMA Table 4, which assigns PM5_Strong (PTC) for BRCA2 exon 11 termination codon variants. Exon 11 harbors numerous proven pathogenic PTC variants.3 PM2_Supporting is met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare pathogenic variant in outbred populations.4 The variant has been classified as Pathogenic by the ENIGMA expert panel and 7 clinical laboratories in ClinVar (VariationID: 266780).5 Under ENIGMA Table 3 combining rules, PVS1 (Very Strong) + PM5_Strong + PM2_Supporting meets the criteria for Pathogenic classification (1 Very Strong + 1 Strong fulfills the Pathogenic threshold).6
BRCA2
Final classification
Pathogenic
BRCA2 c.3881T>G · p.Leu1294Ter
BRCA2
NM_000059.3:c.3881T>G (p.Leu1294Ter) is a nonsense variant in BRCA2 exon 11 that introduces a premature termination codon at residue 1294 of 3418, predicted to result in loss of the C-terminal DNA-binding domain and nuclear localization signals.
ENIGMA BRCA1/BRCA2 Specification v1.2.0 Table 3 combining rules applied to adjudicated criteria. PVS1 (Very Strong) + PM5_Strong exceeds the Pathogenic threshold (1 Very Strong + 1 Strong). Additionally, PVS1 + PM2_Supporting + PP5_Supporting independently satisfies 1 Very Strong + 2 Supporting → Pathogenic. No benign criteria met; no conflicting evidence.
Classification rationale
PVS1PM5PM2PP5
Pathogenic
BRCA2 c.3881T>G
PVS1 + PM5 + PM2 + PP5
→
Pathogenic
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 11 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
Nonsense variant NM_000059.3:c.3881T>G (p.Leu1294Ter) in BRCA2 exon 11 introduces a premature termination codon predicted to truncate the protein at residue 1294 of 3418, removing the C-terminal DNA-binding domain (aa 2481-3186) and nuclear localization signals. Loss of function is the established disease mechanism for BRCA2. Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PVS1 (Very Strong). No predicted or observed rescue via alternative splicing (SpliceAI max delta = 0.00).
Nonsense variant p.Leu1294Ter in BRCA2 exon 11ENIGMA Table 4 assigns PVS1 (Very Strong) for BRCA2 exon 11 PTC variantsSpliceAI max delta score 0.00 — no predicted splice alteration
✓
PM2
supporting
review
Pathogenic
Variant is absent from gnomAD v2.1 (exome), gnomAD v4.1, and gnomAD-Canada v1.0. Per ENIGMA PM2 rule, absence from controls in outbred populations supports PM2_Supporting. gnomAD v2.1/v4.1 returned null allele counts consistent with absence from the database. gnomAD-Canada confirms zero allele observations.
Absent from gnomAD v2.1 exome (non-cancer subset)Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0 (AC=0
✓
PM5
strong
Pathogenic
Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PM5_Strong (PTC). Exon 11 is not among the PM5_N/A exons (E12, E27, E6), and numerous proven pathogenic PTC variants have been reported in this exon. This provides additional weight beyond PVS1 for the protein termination codon.
ENIGMA Table 4 assigns PM5_Strong (PTC) for BRCA2 exon 11Exon 11 is within the PM5_PTC-applicable exon setMultiple proven pathogenic PTC variants reported in BRCA2 exon 11
Assessed · not applied
Pathogenic
PS3
No variant-specific functional assay data available for NM_000059.3:c.3881T>G.
PS4
No case-control study data with odds ratios available for this specific variant.
PP1
No cosegregation data available for this variant.
PP3
ENIGMA PP3 applies to: (a) missense/in-frame variants inside a clinically important functional domain with BayesDel no-AF score ≥ 0.30, or (b) variants with predicted splicing impact (SpliceAI ≥ 0.2).
PP4
No clinical history likelihood ratio data available for this variant.
Benign
BA1
Variant is absent from gnomAD.
BS1
Variant is absent from gnomAD.
BS2
No proband-level data with Fanconi anemia phenotype assessment available.
BS3
No variant-specific functional assay data showing no damaging effect.
BS4
No cosegregation data available.
BP5
No multifactorial likelihood data supporting benignity available for this variant.
N/A · 11
PS1 · PS2 · PM1 · PM6 · PP2 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
v4.1
This variant is absent from gnomAD v4.1.
v2.1
This variant is absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (7 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 266780)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.0577565.
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 · 8 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
20104584 ↗
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
28039656 ↗
Novel and reported pathogenic variants in exon 11 of BRCA2 gene in a cohort of Sri Lankan young breast cancer patients.
CLINVAR