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
Final classification
Pathogenic
PVS1PM5PP5
BRCA2
c.7673_7674del
p.Glu2558ValfsTer7
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 12 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
Pathogenic
This variant is a frameshift deletion predicted to produce p.(Glu2558ValfsTer7). Under the ENIGMA BRCA2 specification, loss of function is an established disease mechanism for BRCA2, and exon 16 is annotated as eligible for PVS1; therefore this truncating variant meets PVS1 at Very Strong strength.
Frameshift consequence p.(Glu2558ValfsTer7)BRCA2 loss of function established in the official ENIGMA frameworkENIGMA Table 4 marks exon 16 as PVS1
PM5
strong
Pathogenic
This variant creates a premature termination codon in BRCA2 exon 16. In the ENIGMA BRCA2 exon-level truncating-variant table, exon 16 is annotated for PM5_PTC at Strong strength, indicating that a different proven pathogenic truncating variant has been established in this exon and supporting additional pathogenic weight.
Frameshift with premature termination codonENIGMA Table 4 exon 16 annotation: PM5_Strong (PTC)
Assessed · not applied
· 5 not met · 7 not assessed
Pathogenic
PS3
No variant-specific calibrated functional assay result for this deletion was identified in the ENIGMA BRCA2 functional assay table, so PS3 was not applied.
PS4
This variant has been reported in ClinVar, but no case-control dataset or other quantified enrichment evidence meeting the ENIGMA PS4 requirement was identified.
PM2
This variant is absent from gnomAD v2.1 but is 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).
PM3
No evidence was identified that this variant was observed with another BRCA2 variant in a patient with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not applied.
PP1
No segregation data were identified for this variant, so PP1 was not applied.
PP4
In the BRCA2 clinical-history likelihood-ratio dataset, this variant has LR 1.833 in 1 proband.
Benign
BA1
This variant does not meet the ENIGMA BA1 threshold.
BS1
This variant does not meet the ENIGMA BS1 threshold.
BS2
No qualifying data were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA BS2 scoring framework, so BS2 was not applied.
BS3
No variant-specific calibrated functional study showing no damaging effect was identified for this deletion, so BS3 was not applied.
BS4
No lack-of-segregation data were identified for this variant, so BS4 was not applied.
BP5
In the BRCA2 clinical-history likelihood-ratio dataset, this variant has LR 1.833 in 1 proband.
N/A · 13
PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
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