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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 and is classified there as Benign by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

Gene
BRCA1
Transcript
NM_007294.3
HGVS · transcript:coding
NM_007294.3:c.301+7G>A
Consequence
N/A
GRCh38
chr17:43104861 C>T
GRCh37
chr17:41256878 C>T
Basis Official ClinGen ENIGMA BRCA1/BRCA2 final-classification framework used: Specification v1.2 Table 3 with the ENIGMA conflicting-evidence point system. ▾
Official ClinGen ENIGMA BRCA1/BRCA2 final-classification framework used: Specification v1.2 Table 3 with the ENIGMA conflicting-evidence point system.
Classification rationale
PP3 BS3BP6 Likely Benign
BRCA1 c.301+7G>A

The BRCA1 c.301+7G>A (NP_009225.1:p.?) variant has been reported in ClinVar and is classified there as Benign by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at AF 5.40093e-05 (87/1610834 alleles; 0 homozygotes), so it is not absent from population controls.2 Functional evidence supports a benign effect: ENIGMA BRCA1 Table 9 assigns BS3_Strong for this variant, and RNA studies reported no aberrant splicing.3 Computational splicing evidence predicts possible splice impact, with a SpliceAI maximum delta score of 0.29, which meets the ENIGMA BRCA1 PP3 threshold and does not meet the BP4 threshold.4

PP3 + BS3 + BP6 → Likely Benign
1 clinvar ↗cspec ↗
2 gnomad_v2 ↗gnomad_v4 ↗
3 vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:22505045 ↗PMID:24667779 ↗
4 spliceai ↗cspec ↗
Gene diagram · NM_007294.3 · variants mapped to exon structure
BRCA1 NM_007294.3
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 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      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
      Absent from gnomAD v2.1.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.0054% · 87 / 1,610,834
      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
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD v4 ↗ gnomAD v2 ↗
      ClinVar screenshot
      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).
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts possible splice impact for this variant (max delta score = 0.29).
      SpliceAI ↗
      Functional No data
      No calibrated functional assay or RNA evidence was identified for this variant.
      OncoKB ↗
      COSMIC screenshot
      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.
      COSMIC ↗
      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
      PMID 22505045 ↗
      Found
      Structured finding pending for this record — see source link.
      Applied to
      →BS3 supports · met
      Functional characterization of BRCA1 gene variants by mini-gene splicing assay.
      PMID 24667779 ↗
      Found
      Structured finding pending for this record — see source link.
      Applied to
      →BS3 supports · met
      Sources & reference links
      7Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC