Back
LYFE SCIENCES
Project: HERA
NM_000059.4:c.7057G>C
p.Gly2353Arg  ·  BRCA2
Starting
Initialising…
0%
Legacy Engine
Ready
View Legacy →
Classification rationale
1

The BRCA2 c.7057G>C (p.Gly2353Arg) variant has been reported in ClinVar, where the aggregate record includes an ENIGMA expert panel Benign classification.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

cspec ↗
4

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.4. BayesDel score = -0.110167.
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueG2353
Hotspots ↗