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 applied · 14 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BS3
strong
Benign
In a calibrated BRCA1 functional study, this variant showed protein function similar to benign control variants, and BRCA1 expert-panel materials assign BS3_Strong. Supplementary functional data list c.67G>A as having no functional impact.
Table 9 assigns BS3 Strong for c.67G>ASupplementary Table 4 lists 'No functional impact'Findlay 2018 cited as calibrated functional evidence
✓
BP4
supporting
Benign
This missense variant lies in the BRCA1 RING domain and shows no predicted damaging effect under the BRCA1 computational 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 splice threshold of 0.1, supporting BP4_Supporting.
BayesDel no-AF 0.0764379 <= 0.15SpliceAI max delta 0.00 <= 0.1Variant is in the BRCA1 RING domain
Assessed · not applied
Pathogenic
PS1
No confirmed pathogenic or likely pathogenic comparator producing the same amino acid change was identified in the reviewed materials, so PS1 was not assessed from the currently available evidence.
PS3
Available functional evidence does not support a damaging effect.
PS4
No case-control study or quantified enrichment data showing that this variant is significantly more common in affected individuals than controls were identified, so PS4 was not assessed.
PM2
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which is consistent with rarity.
PM3
No evidence was identified that this variant has been observed in the biallelic Fanconi anemia context required for BRCA1 PM3 scoring, so PM3 was not assessed.
PP1
No segregation data were identified for this variant, so PP1 was not assessed.
PP3
This missense variant lies in the BRCA1 RING domain, but the computational thresholds for PP3 are not met.
PP4
No variant-specific BRCA1 clinical-history likelihood ratio meeting PP4 thresholds was identified in the reviewed materials, so PP4 was not assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the BRCA1 BA1 threshold of filter allele frequency greater than 0.1%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the BRCA1 BS1 thresholds of filter allele frequency greater than 0.002% or 0.01%.
BS2
No qualifying observations in unaffected individuals meeting the BRCA1 BS2 point-based framework were identified, so BS2 was not assessed.
BS4
No lack-of-segregation data were identified for this variant, so BS4 was not assessed.
BP1
BP1_Strong requires a missense or similar variant outside a clinically important BRCA1 functional domain with no splice effect.
BP5
No variant-specific BRCA1 clinical-history likelihood ratio at or below the BP5 thresholds was identified in the reviewed materials, so BP5 was not assessed.
N/A · 12
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7
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