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LYFE SCIENCES
Project: HERA
NM_007294.4:c.301+7G>A
p.?  ·  BRCA1
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

PMID:22505045 ↗ PMID:24667779 ↗
4

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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 ↗
03
Functional
No functional summary recorded.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.29).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
06
Cancer hotspots
No cancer hotspot summary recorded.