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.1 This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity in population databases.2 In a calibrated BRCA1 functional study, this variant showed no functional impact and BRCA1 expert-panel materials assign BS3_Strong for c.67G>A.3 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/BP4.4
BRCA1
Final classification
Likely Benign
BRCA1 c.67G>A · p.Glu23Lys
BRCA1
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.
Applied the official ENIGMA BRCA1/BRCA2 v1.2 final-classification framework (Table 3 criteria-combination rules from the CSPEC/VCEP framework override).
Classification rationale
BS3BP4
Likely Benign
BRCA1 c.67G>A
BS3 + BP4
→
Likely Benign
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:30209399 ↗
4
cspec ↗bayesdelspliceai ↗revelvcep_appendices_v1_2_2024_11_18
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 2 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 benign
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 867739)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.734. BayesDel score = 0.0764379.
Functional
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.
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.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 4 further PMIDs triaged but not cited — see Sources & References.
PMID PMID:30209399
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
Sources & reference links
9Sources
Triaged references · 4 PMIDs not cited in assessment
14722926 ↗
Novel germline mutations in the BRCA1 and BRCA2 genes in Indian breast and breast-ovarian cancer families.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR