The BRCA1 c.301+7G>A (NP_009225.1:p.?) variant has been reported in ClinVar, where the overall classification is Benign with expert panel review.1 This variant is present in gnomAD, with AF 0.0000885 in v2.1 (25/282562 alleles; grpmax FAF 0.00010876) and AF 0.0000540 in v4.1 (87/1610834 alleles; grpmax FAF 0.00005311), so it is not absent from controls and does not meet BA1.2 Well-established functional evidence supports no damaging effect: ENIGMA Table 9 assigns BS3 Strong based on no aberrant splicing in two studies and a calibrated study showing no functional impact.3 In silico splicing prediction is conflicting with the functional evidence, because SpliceAI gives a maximum delta score of 0.29, which exceeds the ENIGMA PP3 threshold of 0.20 and argues against BP4.4
BRCA1
Final classification
Likely Benign
BRCA1 c.301+7G>A · p.?
BRCA1
The BRCA1 c.301+7G>A (NP_009225.1:p.?) variant has been reported in ClinVar, where the overall classification is Benign with expert panel review.
ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2.0 final-classification framework (Table 3 override with conflicting-evidence point system)
Classification rationale
PP3
BS3BP6
Likely Benign
BRCA1 c.301+7G>A
PP3 + BS3 + BP6
→
Likely Benign
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:22505045 ↗PMID:24667779 ↗
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 3 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
This variant is present in gnomAD v4.1 (AF= 5.40093e-05; MAF= 0.00540%, 87/1610834 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000135199; MAF= 0.01352%, 4/29586 alleles, homozygotes = 0); grpmax FAF= 5.311e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 8.84762e-05; MAF= 0.00885%, 25/282562 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000193013; MAF= 0.01930%, 2/10362 alleles, homozygotes = 0); grpmax FAF= 0.00010876.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0054%
· 87 / 1,610,834
0 hom · FAF 0.0053%
0 hom · FAF 0.0053%
Ashkenazi Jewish 4 / 29,586 |
0.014% |
European (non-Finnish) 77 / 1,177,260 |
0.0065% |
Remaining individuals 3 / 62,376 |
0.0048% |
European (Finnish) 3 / 63,922 |
0.0047% |
+ 6 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, African/African American)
gnomAD v2.1
0.0088%
· 25 / 282,562
0 hom · FAF 0.011%
0 hom · FAF 0.011%
Ashkenazi Jewish 2 / 10,362 |
0.019% |
European (non-Finnish) 21 / 128,976 |
0.016% |
Remaining individuals 1 / 7,204 |
0.014% |
European (Finnish) 1 / 25,058 |
0.004% |
+ 4 not observed (African/African American, Admixed American, East Asian, South Asian)
ClinVar
This variant has been reported in ClinVar as Benign (11 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.29).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:22505045
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
PMID PMID:24667779
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
Sources & reference links