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LYFE SCIENCES
Project: HERA
NM_007294.4:c.67G>A
p.Glu23Lys  ·  BRCA1
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Classification rationale
1

The BRCA1 c.67G>A (p.Glu23Lys, E23K) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with a single submitter interpretation of uncertain significance.

clinvar ↗
2

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity in population databases.

gnomad_v2 ↗ gnomad_v4 ↗ gnomad_canada ↗
3

In a calibrated BRCA1 functional study, this variant showed no functional impact and BRCA1 expert-panel materials assign BS3_Strong for c.67G>A.

PMID:30209399 ↗
4

Available computational evidence does not support a damaging effect under the BRCA1 ENIGMA rule: BayesDel no-AF is 0.076, which is at or below the BP4 threshold of 0.15, and SpliceAI is 0.00, which is at or below the threshold of 0.1; REVEL is 0.734 but is not the governing BRCA1 VCEP threshold for PP3/BP4.

cspec ↗ spliceai ↗
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
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 867739)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.734. BayesDel score = 0.0764379.
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.
ResidueE23
Hotspots ↗