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
Final classification
Uncertain Significance
BRCA2
c.794-2A>G
p.?
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 0 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 0
No criteria were applied for this variant.
Assessed · not applied
· 6 not met · 7 not assessed
Pathogenic
PS1
Available evidence does not identify a previously classified pathogenic or likely pathogenic BRCA2 variant with the same demonstrated splice consequence as this variant.
PS3
No calibrated functional assay evidence supporting a damaging effect was identified for this variant under the ENIGMA PS3 framework.
PS4
No case-control study or quantified enrichment analysis showing that this variant is significantly more common in affected individuals than in controls was identified.
PM2
This variant is absent from gnomAD v2.1 but is present once in gnomAD v4.1 at an overall allele frequency of 6.260650932398744e-07 (1/1597278 alleles; 0 homozygotes).
PM3
No evidence was identified that this variant was observed in trans with another pathogenic BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia.
PP1
No segregation data were identified for this variant, so a quantitative co-segregation likelihood ratio supporting pathogenicity could not be established.
PP4
No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified.
Benign
BA1
The observed population frequency is far below the ENIGMA BA1 threshold.
BS1
The observed population frequency is far below the ENIGMA BS1 thresholds.
BS2
No evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in a way that would satisfy the ENIGMA BS2 point-based framework.
BS3
No well-established functional study showing no damaging effect was identified for this variant.
BS4
No lack-of-segregation data were identified for this variant, so a quantitative likelihood ratio supporting BS4 could not be established.
BP5
No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified.
N/A · 15
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
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