The BRCA1 c.5407-10G>A (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the current aggregate classification is Likely Pathogenic with expert-panel review.1 This variant is absent from gnomAD v4.1 and is present only once in gnomAD v2.1 (1/251448 alleles; AF 3.98e-06), which is too low for benign population criteria but does not satisfy the BRCA1 ENIGMA requirement for complete absence from gnomAD for PM2.2 In published BRCA1 functional and RNA studies, this variant showed retention of 8 nucleotides from intron 22 and partial functional impact rather than a clearly damaging or clearly benign result, so the ENIGMA BRCA1 functional tables indicate that PS3 and BS3 are not met.3 SpliceAI predicts a strong splice effect for this variant with a maximum delta score of 1.00, which exceeds the BRCA1 ENIGMA PP3 threshold of 0.20 for intronic variants outside the native +/-1,2 splice sites and supports PP3 at Supporting strength.4
BRCA1
Final classification
Uncertain Significance
BRCA1 c.5407-10G>A · p.?
BRCA1
The BRCA1 c.5407-10G>A (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the current aggregate classification is Likely Pathogenic with expert-panel review.
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 criteria-combination framework: applied criteria PP3 supporting and PP5 supporting do not satisfy any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination, so the variant is classified as Uncertain Significance.
Classification rationale
PP3PP5
Uncertain Significance
BRCA1 c.5407-10G>A
PP3 + PP5
→
Uncertain Significance
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:30209399 ↗PMID:31143303 ↗
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
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
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.97697e-06; MAF= 0.00040%, 1/251448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79152e-06; MAF= 0.00088%, 1/113746 alleles, homozygotes = 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
0.0004%
· 1 / 251,448
0 hom
0 hom
European (non-Finnish) 1 / 113,746 |
0.00088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as likely pathogenic (1 clinical laboratory) and as Likely Pathogenic 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 = 1.00).
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.
Sources & reference links