NM_000059.4:c.3111A>G normalizes to the synonymous BRCA2 protein consequence p.(Gln1037=) / p.(Q1037=).1 Q1037 is outside the BRCA2 clinically important domains defined by the specification (PALB2-binding aa 10-40 and DNA-binding aa 2481-3186).2 SpliceAI predicts no significant splice impact for this variant, with max delta score 0.00, satisfying the no-splicing-predicted part of BP1_Strong.3 The BRCA2 ENIGMA specification states to apply BP1_Strong for silent variants outside clinically important domains with SpliceAI ≤0.1, and its Table 3 states Likely Benign can be assigned from one Strong benign code when multiple evidence types contribute; BP1_Strong is given as an explicit example.4 Population data do not support BA1 or BS1, and the variant is not absent from controls, so PM2 is also not met; these findings do not overturn the BP1_Strong-based Likely Benign classification.5
Final classification
Likely Benign
BP1
BRCA2
c.3111A>G
p.Gln1037=
This variant
NM_000059.4:c.3111A>G normalizes to the synonymous BRCA2 protein consequence p.(Gln1037=) / p.(Q1037=).
BRCA2 ENIGMA/ClinGen VCEP v1.2 adapted ACMG/AMP framework. BP1_Strong is met, and the specification's Table 3 allows Likely Benign from one Strong benign code when multiple evidence types contribute to that code; the specification explicitly cites BP1_Strong as such an example.
Classification rationale
BP1
Likely Benign
BRCA2 c.3111A>G
BP1
→
Likely Benign
1
cspec ↗
2
vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___v_1___2___2_0_2_4___1_1___1_8
4
vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___v_1___2___2_0_2_4___1_1___1_8
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_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 15 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
BP1
Strong
Benign
This is a silent/synonymous BRCA2 variant, p.(Gln1037=)/p.(Q1037=), located outside the BRCA2 clinically important domains (PALB2-binding aa 10-40 and DNA-binding aa 2481-3186). SpliceAI predicts no splice effect with max delta 0.00. Under the BRCA2 ENIGMA specification, BP1_Strong applies to silent variants outside clinically important domains when no splicing is predicted.
Normalized consequence: NP_000050.3:p.(Gln1037=) / p.(Q1037=).Q1037 lies outside aa 10-40 and aa 2481-3186 BRCA2 clinically important domains.SpliceAI max delta score = 0.00.
Assessed · not applied
· 15 not met · 0 not assessed
Pathogenic
PS1
No same-amino-acid pathogenic comparator or same predicted splice consequence pathogenic comparator was identified in the reviewed workspace materials.
PS3
No variant-specific damaging functional assay assignment was identified in Specifications Table 9 or other reviewed VCEP materials.
PS4
No case-control enrichment evidence for this specific variant was identified in the workspace, and the variant is absent from ClinVar submissions that might have pointed to such data.
PM2
PM2_Supporting requires absence from gnomAD controls.
PP1
No quantitative segregation data were present in the workspace.
PP3
PP3 is not met because SpliceAI shows no predicted splice impact (max delta 0.00), and this synonymous variant is outside the clinically important domains where missense-domain PP3 logic would apply.
PP4
No multifactorial likelihood clinical data supporting phenotype-specific enrichment were present in the workspace.
Benign
BA1
The observed population frequency is far below the BRCA2 BA1 threshold.
BS1
The observed population frequency is below both BRCA2 BS1 thresholds.
BS2
No adult biallelic or phenotype-negative observational dataset relevant to BRCA2 BS2 was present in the workspace.
BS3
No variant-specific benign protein functional assay assignment was identified in the reviewed BRCA2 functional table.
BS4
No quantitative lack-of-segregation evidence was present in the workspace.
BP4
For silent variants, BRCA2 BP4 applies only inside a clinically important functional domain with no predicted splice impact.
BP5
No multifactorial likelihood clinical data arguing against pathogenicity were assembled for this specific variant.
BP7
BRCA2 BP7 for silent variants is used in addition to BP4 for silent variants inside a clinically important domain, or as BP7_Strong with qualifying RNA assay data.
N/A · 12
PVS1 · PS2 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.96163e-06; MAF= 0.00050%, 8/1612374 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164799; MAF= 0.01648%, 1/6068 alleles, homozygotes = 0); grpmax FAF= 4.089e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.00702e-06; MAF= 0.00040%, 1/249562 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.18123e-05; MAF= 0.00618%, 1/16178 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0005%
· 8 / 1,612,374
0 hom · FAF 0.0041%
0 hom · FAF 0.0041%
Middle Eastern 1 / 6,068 |
0.016% |
African/African American 5 / 74,872 |
0.0067% |
East Asian 1 / 44,848 |
0.0022% |
European (non-Finnish) 1 / 1,179,106 |
8.5e-05% |
+ 6 not observed (Remaining individuals, Admixed American, European (Finnish), South Asian, Ashkenazi Jewish, Amish)
gnomAD v2.1
0.0004%
· 1 / 249,562
0 hom
0 hom
African/African American 1 / 16,178 |
0.0062% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
COSMIC
Cancer hotspots
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