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LYFE SCIENCES
Project: HERA
NM_007294.4:c.212+3A>G
p.?  ·  BRCA1
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Classification rationale
1

The BRCA1 c.212+3A>G (p.?) variant has been reported in ClinVar as pathogenic by the ClinGen ENIGMA expert panel and by multiple clinical laboratories.

clinvar ↗ cspec ↗
2

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a very low frequency of 2/1574274 alleles (AF 1.27043e-06; 0.00013%), which is below the BA1 and BS1 population thresholds.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

ENIGMA-calibrated functional evidence supports a damaging effect: Table 9 assigns PS3_Strong for BRCA1 c.212+3A>G, and supplementary ENIGMA datasets classify the variant as having complete functional impact with multiple RNA assays showing aberrant splicing consistent with loss of function.

PMID:12037674 ↗
4

SpliceAI predicts a deleterious splicing effect with a maximum delta score of 0.63, which exceeds the ENIGMA PP3 threshold of 0.2 for intronic variants outside the canonical +/-1,2 splice positions.

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
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.27043e-06; MAF= 0.00013%, 2/1574274 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.74444e-06; MAF= 0.00017%, 2/1146498 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (13 clinical laboratories) and as not provided (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Pathogenic 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 = 0.63).
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.