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
Final classification
Likely Benign
PP3BS3BP6
BRCA1
c.301+7G>A
p.?
This variant
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 ↗
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its underlying evidence before relying on any call.
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
PP3
supporting
Pathogenic
SpliceAI predicts splice impact for this intronic variant, with a maximum delta score of 0.29. This is above the ENIGMA PP3 threshold of 0.20 for intronic variants outside the canonical ±1,2 splice sites, so PP3 is met at Supporting strength.
SpliceAI max delta score 0.29ENIGMA PP3 threshold for splicing is ≥0.2
BS3
strong
Benign
Well-established functional evidence supports no damaging effect. ENIGMA Table 9 assigns BS3 Strong for this intronic variant, citing no aberrant splicing in two studies and a calibrated study showing function similar to benign control variants with no functional impact.
ENIGMA Table 9: BS3 StrongSupplementary tables: no aberration in splicing studiesfunctional classification: no functional impact
Assessed · not applied
· 6 not met · 9 not assessed
Pathogenic
PVS1
BRCA1 is a gene in which loss of function is an established disease mechanism, but this variant is an intronic +7 substitution rather than a nonsense, frameshift, or canonical ±1,2 splice-site variant.
PS1
No evidence was identified showing that this variant has the same established pathogenic protein or splicing effect as a previously classified pathogenic or likely pathogenic BRCA1 variant, so PS1 was not assessed.
PS3
Available functional studies do not support a damaging effect.
PS4
No case-control evidence was identified showing a statistically significant increase of this variant in affected individuals compared with controls, so PS4 was not assessed.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified for BRCA1-related Fanconi anemia with qualifying co-occurring variants in the same gene, so PM3 was not assessed.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.
PP4
No calibrated multifactorial clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this variant, so PP4 was not assessed.
Benign
BA1
Population data do not reach the ENIGMA BA1 threshold.
BS1
This variant is present in gnomAD, but the available summaries do not establish a non-founder population filter allele frequency that clearly exceeds the ENIGMA BS1 thresholds.
BS2
No evidence was identified showing qualifying observations in individuals without features of BRCA1-related Fanconi anemia under the ENIGMA point-based framework, so BS2 was not assessed.
BS4
No quantitative lack-of-segregation data were identified for this variant, so BS4 was not assessed.
BP4
BP4 is not met because SpliceAI predicts splice impact, with a maximum delta score of 0.29.
BP5
No calibrated multifactorial clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified for this variant, so BP5 was not assessed.
BP7
This intronic +7 variant is in a position that can be considered for BP7, but BP7 Supporting requires BP4 and BP4 is not met because SpliceAI is 0.29, above the benign threshold of 0.10.
N/A · 10
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3
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.
Guidelines for splicing analysis in molecular diagnosis derived from a set of 32
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
Functional characterization of BRCA1 gene variants by mini-gene splicing assay.
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
Sources & reference links