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.1 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.2 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.3 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.4
BRCA1
Final classification
Likely Pathogenic
BRCA1 c.212+3A>G · p.?
BRCA1
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.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (official ClinGen CSPEC/VCEP criteria-combination rules).
Classification rationale
PS3PP3PP5
Likely Pathogenic
BRCA1 c.212+3A>G
PS3 + PP3 + PP5
→
Likely Pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:12037674 ↗
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
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 pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This 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.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00013%
· 2 / 1,574,274
0 hom · FAF 2.9e-05%
0 hom · FAF 2.9e-05%
European (non-Finnish) 2 / 1,146,498 |
0.00017% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.63).
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
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:12037674
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links