The variant is BRCA2 NM_000059.4:c.341A>G, p.(His114Arg), a missense substitution at residue 114. Under the BRCA2 ENIGMA specification, BP1_Strong applies to missense variants outside clinically important functional domains with no predicted splice impact. Residue 114 is outside the BRCA2 domains used by this framework (aa 10-40 and aa 2481-3186), and SpliceAI predicts no significant splice effect (max delta 0.03).1 Population data support BS1_Supporting because gnomAD v2.1 grpmax FAF is 7.443e-05, which falls within the BRCA2 BS1_Supporting range (>0.00002 and ≤0.0001).2 The ENIGMA multifactorial dataset does not support pathogenic enrichment: for c.341A>G the combined LR is 0.5897487000827281 and the sheet comments that the combined LR is not <0.5 or >2, so PS4/BS4-type multifactor evidence is not met.3 No calibrated damaging or benign functional assay assignment for this variant was identified in the curated ENIGMA functional table, so PS3 and BS3 were not applied.4 Overall, the assembled workspace supports a benign-leaning VCEP classification without conflicting pathogenic evidence sufficient to retain VUS; the best fit is Likely benign.5
BRCA2
Final classification
Likely benign
BRCA2 c.341A>G · p.His114Arg
BRCA2
The variant is BRCA2 NM_000059.4:c.341A>G, p.(His114Arg), a missense substitution at residue 114.
ENIGMA BRCA2 VCEP ACMG/AMP qualitative combination rules. BP1_Strong is met, and BS1_Supporting is also met; this benign evidence supports a Likely benign classification.
Classification rationale
BS1BP1
Likely benign
BRCA2 c.341A>G
BS1 + BP1
→
Likely benign
1
cspec ↗
3
vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
4
vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_9___v_1___2___2_0_2_4___1_1___1_8
5
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 · 2 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
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
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