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
Final classification
Benign
BS1BS3BS4BP1BP6
BRCA2
c.7057G>C
p.Gly2353Arg
This variant
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 ↗
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may be applied incorrectly, sources may be misread, and a confident-looking
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its underlying evidence before relying on any call.
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 11 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 · 5
Strength
Supporting
Moderate
Strong
Very strong
BS1
supporting
review
Benign
This variant meets ENIGMA BS1_Supporting because the filter allele frequency is above 0.00002 and not above 0.0001. The grpmax FAF is 2.859e-05 in gnomAD v2.1 and 8.841e-05 in gnomAD v4.1, both within the BS1_Supporting range.
gnomAD v2.1 grpmax FAF 2.859e-05.gnomAD v4.1 grpmax FAF 8.841e-05.ENIGMA BS1_Supporting range is FAF >0.00002 and ≤0.0001.
BS3
strong
review
Benign
In a calibrated BRCA2 functional study, this variant showed protein function similar to benign control variants, with complementation observed and an HDR score of 82. ENIGMA Table 9 assigns BS3 Strong for this variant.
ENIGMA Table 9 entry: BS3 Strong for BRCA2 c.7057G>C p.(Gly2353Arg).Mesman assay summary: complementation yesHDR 82
BS4
supporting
review
Benign
Available segregation evidence supports lack of segregation with disease. The segregation likelihood ratio is 0.345, which is below the ENIGMA BS4_Supporting threshold of 0.48.
Parsons multifactorial dataset segregation LR 0.345.ENIGMA BS4_Supporting requires LR ≤0.48.
BP1
strong
review
Benign
This missense variant is outside the BRCA2 ENIGMA clinically important missense domains and has no predicted splice impact. Residue 2353 lies outside the PALB2 binding domain (aa 10-40) and DNA-binding region (aa 2481-3186), and SpliceAI is 0.01, below the no-splicing-impact threshold of 0.1, so BP1_Strong is met.
Protein position 2353 is outside BRCA2 aa 10-40 and aa 2481-3186 ENIGMA domains.SpliceAI max delta score 0.01.ENIGMA BP1_Strong applies to missense variants outside these domains with SpliceAI ≤0.1.
Assessed · not applied
· 6 not met · 5 not assessed
Pathogenic
PS1
No evidence was identified showing that this amino acid change is the same protein consequence as a previously established pathogenic BRCA2 variant acting through the protein rather than splicing.
PS3
Available functional evidence does not support a damaging effect.
PS4
Available data do not show statistically significant enrichment in affected individuals at the ENIGMA PS4 threshold.
PM2
This variant is present in population databases and therefore does not meet ENIGMA PM2, which requires absence from controls.
PM3
No evidence was identified showing this variant in trans with another BRCA2 variant in a patient with BRCA2-related Fanconi anemia, so PM3 could not be applied.
PP1
Available family data do not support co-segregation with disease.
PP3
Computational evidence does not support a damaging effect.
PP4
No approved BRCA2 clinical-history likelihood-ratio result meeting ENIGMA PP4 thresholds was identified for this exact variant in the reviewed clinical-history table.
Benign
BA1
The population frequency does not reach the ENIGMA BA1 stand-alone benign threshold.
BS2
No data were identified showing this variant in sufficient individuals without features of BRCA2-related Fanconi anemia to apply BS2.
BP5
No approved BRCA2 clinical-history likelihood-ratio result meeting ENIGMA BP5 thresholds was identified for this exact variant in the reviewed clinical-history table.
N/A · 12
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4 · BP7
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