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LYFE SCIENCES
Project: HERA
NM_000059.4:c.7992T>A
p.Ile2664=  ·  BRCA2
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Classification rationale
1

The BRCA2 c.7992T>A (p.Ile2664=) variant has been reported in ClinVar, including a likely benign expert panel classification from ENIGMA and multiple likely benign clinical laboratory submissions.

clinvar ↗
2

In population databases, the variant is present at low frequency; in gnomAD v2.1 the grpmax filter allele frequency is 3.433e-05, which exceeds the BRCA2 ENIGMA BS1 Supporting threshold of 2.0e-05, and gnomAD v4.1 shows a consistent low-frequency signal with grpmax filter allele frequency 3.666e-05.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

SpliceAI predicts no significant splice effect with a maximum delta score of 0.02, which is below the BRCA2 ENIGMA BP4/BP7 threshold of 0.1 and below the PP3 threshold of 0.2, supporting BP4 and BP7 rather than a deleterious splicing prediction.

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
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 3.19412e-05; MAF= 0.00319%, 8/250460 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.06801e-05; MAF= 0.00707%, 8/113186 alleles, homozygotes = 0); grpmax FAF= 3.433e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 3.65626e-05; MAF= 0.00366%, 59/1613670 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.66135e-05; MAF= 0.00466%, 55/1179916 alleles, homozygotes = 0); grpmax FAF= 3.666e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (10 clinical laboratories) and as Uncertain significance (4 clinical laboratories) and as Benign (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 52463)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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.
ResidueI2664
Hotspots ↗