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LYFE SCIENCES
Project: HERA
NM_000059.4:c.7673_7674del
p.Glu2558ValfsTer7  ·  BRCA2
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Initialising…
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Legacy Engine
Processing…
Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

cspec ↗
4

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This 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).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.24).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueE2558
Hotspots ↗