The BRCA2 c.7673_7674delAG (p.Glu2558ValfsTer7; p.E2558Vfs*7) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic, including ENIGMA expert panel review.1 This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1,613,678 alleles; total AF 6.197e-07; highest observed population AF 1.098e-05 in South Asian individuals), supporting extremely low population frequency but not complete absence from population databases.2 Under the ENIGMA BRCA2 loss-of-function framework, this exon 16 frameshift is eligible for PVS1, and the exon-level truncating-variant table assigns additional PM5_PTC evidence at Strong strength for this exon.3 SpliceAI predicts possible splice impact with a maximum delta score of 0.24, while REVEL and BayesDel are not applicable to this deletion; this computational result was reviewed but not used as separate PP3 evidence because the variant was adjudicated through the loss-of-function framework.4
BRCA2
Final classification
Pathogenic
BRCA2 c.7673_7674del · p.Glu2558ValfsTer7
BRCA2
The BRCA2 c.7673_7674delAG (p.Glu2558ValfsTer7; p.E2558Vfs*7) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic, including ENIGMA expert panel review.
ENIGMA BRCA1/BRCA2 Specification v1.2 final-classification framework (Table 3 adapted ACMG/AMP criteria-combination rules)
Classification rationale
PVS1PM5PP5
Pathogenic
BRCA2 c.7673_7674del
PVS1 + PM5 + PP5
→
Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_specifications_table4_v1_2_2024_11_18
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 3 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
This variant is present in gnomAD v4.1 (AF= 6.19702e-07; MAF= 0.00006%, 1/1613678 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.0982e-05; MAF= 0.00110%, 1/91058 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,613,678
0 hom
0 hom
South Asian 1 / 91,058 |
0.0011% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (13 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.24).
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