NM_000059.4:c.8673_8674del is a 2-bp frameshift deletion in BRCA2 exon 21 (DNA-binding domain, aa 2481-3186), producing a premature termination codon p.Arg2892ThrfsTer14. BRCA2 loss of function is a well-established mechanism for hereditary breast and ovarian cancer. Per ENIGMA Specifications Table 4 v1.2, PTC variants in exon 21 receive PVS1 at Very Strong strength.1 The variant is absent from gnomAD v2.1 and v4.1 population databases, supporting pathogenicity (PM2 at Supporting strength per ENIGMA).2 Per ENIGMA Table 4, PTC variants in BRCA2 exon 21 are assigned PM5_Supporting (PTC), as other proven pathogenic PTC variants have been observed in this exon.3 ClinVar classifies this variant as Pathogenic with 3-star expert panel review by ENIGMA (Variation ID 52656). PP5 is met at Supporting strength.4 Using the ENIGMA point system: PVS1 (Very Strong = 8) + PM2 (Supporting = 1) + PM5 (Supporting = 1) + PP5 (Supporting = 1) = 11 points. Score ≥10 meets the ENIGMA Pathogenic threshold. This also satisfies the ENIGMA Table 3 rule requiring 1 Very Strong criterion plus at least 2 Supporting criteria for Pathogenic classification.5
BRCA2
Final classification
Pathogenic
BRCA2 c.8673_8674del · p.Arg2892ThrfsTer14
BRCA2
NM_000059.4:c.8673_8674del is a 2-bp frameshift deletion in BRCA2 exon 21 (DNA-binding domain, aa 2481-3186), producing a premature termination codon p.Arg2892ThrfsTer14. BRCA2 loss of function is a well-established mechanism for hereditary breast and ovarian cancer. Per ENIGMA Specifications Table 4 v1.2, PTC variants in exon 21 receive PVS1 at Very Strong strength.
ENIGMA BRCA1/BRCA2 Specification Table 3 v1.2: 1 Very Strong criterion (PVS1) plus 3 Supporting criteria (PM2, PM5, PP5) satisfies the Pathogenic combination rule requiring ≥1 Very Strong + ≥2 Supporting. Confirmed by ENIGMA point system: PVS1(8) + PM2(1) + PM5(1) + PP5(1) = 11 points (≥10 = Pathogenic). No benign criteria are met.
Classification rationale
PVS1PM2PM5PP5
Pathogenic
BRCA2 c.8673_8674del
PVS1 + PM2 + PM5 + PP5
→
Pathogenic
1
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
3
vcep_specifications_table4_v1_2_2024_11_18
5
final_classification_framework
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 12 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_000059.4:c.8673_8674del is a 2-bp deletion in exon 21 causing a frameshift that produces p.Arg2892ThrfsTer14, a premature termination codon (PTC). Loss of function is an established disease mechanism for BRCA2. Per ENIGMA Specifications Table 4, PTC variants in BRCA2 exon 21 are assigned PVS1 at full (Very Strong) strength. The truncation removes 526 C-terminal amino acids including OB folds and nuclear localization signals within the DNA-binding domain (aa 2481-3186), and is predicted to trigger nonsense-mediated decay.
Frameshift deletion in exon 21 creates PTC p.Arg2892ThrfsTer14 within DNA-binding domain (aa 2481-3186)ENIGMA Table 4 assigns PVS1 (full strength) to PTC variants in BRCA2 exon 21BRCA2 LOF is a well-established disease mechanism per CSPEC
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v4.1. Per ENIGMA PM2 rule, absence from population databases in an outbred population supports pathogenicity at Supporting strength.
Absent from gnomAD v2.1 (non-cancerexome only subset)Absent from gnomAD v4.1
✓
PM5
supporting
Pathogenic
Per ENIGMA Specifications Table 4, PTC variants in BRCA2 exon 21 are assigned PM5_Supporting (PTC), as other proven pathogenic PTC variants have been observed in this exon. The variant c.8673_8674del creates a PTC (p.Arg2892ThrfsTer14) in exon 21, satisfying the PM5_PTC rule.
ENIGMA Table 4 assigns PM5_Supporting (PTC) to PTC variants in BRCA2 exon 21Exon 21 is listed as PM5_PTC applicable (not in PM5_N/A exons E6E12
✓
PP5
supporting
Pathogenic
Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.
ClinVar Variation ID 52656: Pathogenicreviewed by ENIGMA expert panel (3-star)16 clinical laboratories concur with Pathogenic classification
Assessed · not applied
Pathogenic
PS3
No variant-specific functional study testing NM_000059.4:c.8673_8674del was identified in the literature.
PS4
No case-control study with odds ratio and p-value meeting ENIGMA thresholds (OR ≥4, p ≤0.05, lower CI excludes 2.0) was identified.
PP1
No co-segregation data available.
PP3
ENIGMA PP3 applies to missense or in-frame variants inside clinically important functional domains (BayesDel ≥0.30) or for predicted splicing (SpliceAI ≥0.2).
PP4
Li et al.
Benign
BA1
Variant is absent from gnomAD.
BS1
Variant is absent from gnomAD.
BS2
No proband-level data available to assess absence of Fanconi Anemia phenotype.
BS3
No variant-specific functional studies showing no damaging effect were identified.
BS4
No segregation data available.
BP4
ENIGMA BP4 applies to missense or in-frame variants inside clinically important functional domains with no predicted impact on protein or splicing.
BP5
Li et al.
N/A · 11
PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · BP1 · BP2 · BP3 · 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.
ClinVar
This variant has been reported in ClinVar as Pathogenic (16 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 52656)
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 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
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR