Starting
Initialising…
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BRCA2
Final classification
Likely Benign
BRCA2 c.3111A>G · p.Gln1037=
BRCA2

NM_000059.4:c.3111A>G normalizes to the synonymous BRCA2 protein consequence p.(Gln1037=) / p.(Q1037=).

Gene
BRCA2
Transcript
NM_000059.4
HGVS · transcript:coding
NM_000059.4:c.3111A>G
Consequence
N/A
GRCh38
chr13:32337466 A>G
GRCh37
chr13:32911603 A>G
Basis 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.
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

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

BP1 Likely Benign
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
Gene diagram · NM_000059.4 · variants mapped to exon structure
BRCA2 NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 1 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 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      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%
      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
      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)
      ClinVar screenshot
      ClinVar
      This variant is absent from ClinVar.
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
      Functional / OncoKB screenshot
      Functional
      OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      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
      6Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB