The BRCA2 c.794-2A>G (p.?) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel classifies it as uncertain significance, while other submitters have reported likely pathogenic or pathogenic interpretations.1 This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 at an overall allele frequency of 6.260650932398744e-07 (1/1597278 alleles; 0 homozygotes), indicating that it is very rare in population databases.2 In the ENIGMA BRCA2 exon-level splice/PVS1 table, this exact splice acceptor variant is associated with observed in-frame exon 10 skipping and assigned PVS1_N/A (RNA), so current VCEP evidence does not support treating it as a qualifying loss-of-function event under PVS1.3 SpliceAI predicts strong splice impact for this variant with a maximum delta score of 0.99 (DS_AL 0.99, DS_AG 0.31), but the BRCA2 ENIGMA framework does not apply PP3 to canonical ±1,2 splice-site variants and this splice prediction should not be double-counted against the variant-specific RNA/PVS1 assessment.4
BRCA2
Final classification
Uncertain Significance
BRCA2 c.794-2A>G · p.?
BRCA2
The BRCA2 c.794-2A>G (p.?) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel classifies it as uncertain significance, while other submitters have reported likely pathogenic or pathogenic interpretations.
ENIGMA BRCA1/BRCA2 Specification v1.2 final-classification framework (Table 3 adapted ACMG/AMP 2015 criteria-combination rules, as provided in the official CSPEC-derived framework override).
Classification rationale
Uncertain Significance
BRCA2 c.794-2A>G
3
vcep_specifications_table4_v1_2_2024_11_18cspec ↗
4
spliceai ↗cspec ↗pvs1_variant_assessment
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 0 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
This variant is present in gnomAD v4.1 (AF= 6.26065e-07; MAF= 0.00006%, 1/1597278 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.55112e-07; MAF= 0.00009%, 1/1169438 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.3e-05%
· 1 / 1,597,278
0 hom
0 hom
European (non-Finnish) 1 / 1,169,438 |
8.6e-05% |
+ 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 Likely pathogenic (4 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely Pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as Uncertain Significance 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 = 0.99). BayesDel score = -0.0908914.
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