The BRCA2 c.7057G>C (p.Gly2353Arg) variant has been reported in ClinVar, where the aggregate record includes an ENIGMA expert panel Benign classification.1 This variant is present in gnomAD, with grpmax filter allele frequencies of 2.859e-05 in v2.1 and 8.841e-05 in v4.1, which are above the ENIGMA BS1_Supporting threshold of 0.00002 and do not reach the BS1 Strong threshold of 0.0001.2 In a calibrated BRCA2 functional study, this variant showed protein function similar to benign control variants, including observed complementation and an HDR score of 82, and ENIGMA Table 9 assigns BS3 Strong.3 Computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact with a max delta score of 0.01, BayesDel no-AF is -0.110167, and codon 2353 lies outside the BRCA2 ENIGMA clinically important missense domains, supporting BP1 rather than PP3.4
BRCA2
Final classification
Benign
BRCA2 c.7057G>C · p.Gly2353Arg
BRCA2
The BRCA2 c.7057G>C (p.Gly2353Arg) variant has been reported in ClinVar, where the aggregate record includes an ENIGMA expert panel Benign classification.
ENIGMA BRCA1/BRCA2 Specification v1.2 final-classification framework (Table 3 override captured in final_classification_framework; ACMG/AMP 2015 with ENIGMA adaptations).
Classification rationale
BS1BS3BS4BP1BP6
Benign
BRCA2 c.7057G>C
BS1 + BS3 + BS4 + BP1 + BP6
→
Benign
3
vcep_specifications_table9_v1_2_2024_11_18vcep_humu_40_1557_s001cspec ↗
4
spliceai ↗bayesdelcspec ↗
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 5 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 benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 7.74713e-05; MAF= 0.00775%, 125/1613500 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00010341; MAF= 0.01034%, 122/1179768 alleles, homozygotes = 0); grpmax FAF= 8.841e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.78332e-05; MAF= 0.00478%, 12/250872 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000491965; MAF= 0.04920%, 3/6098 alleles, homozygotes = 0); grpmax FAF= 2.859e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0077%
· 125 / 1,613,500
0 hom · FAF 0.0088%
0 hom · FAF 0.0088%
European (non-Finnish) 122 / 1,179,768 |
0.01% |
African/African American 2 / 74,856 |
0.0027% |
Admixed American 1 / 59,970 |
0.0017% |
+ 7 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0048%
· 12 / 250,872
0 hom · FAF 0.0029%
0 hom · FAF 0.0029%
Remaining individuals 3 / 6,098 |
0.049% |
African/African American 1 / 16,144 |
0.0062% |
European (non-Finnish) 7 / 113,486 |
0.0062% |
Admixed American 1 / 34,518 |
0.0029% |
+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
ClinVar
This variant has been reported in ClinVar as Likely benign (11 clinical laboratories) and as Benign (7 clinical laboratories) and as Uncertain significance (4 clinical laboratories) and as likely benign (1 clinical laboratory) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.4. BayesDel score = -0.110167.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99061638, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links