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
Final classification
Likely benign
BS1BP1
BRCA2
c.341A>G
p.His114Arg
This variant
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
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 · 2 applied · 14 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
BS1
Supporting
review
Benign
BRCA2 BS1_Supporting is met because gnomAD v2.1 grpmax FAF is 7.443e-05, which is >0.00002 and ≤0.0001.
gnomAD v2.1 grpmax FAF 7.442999999999999e-05.Variant also observed in gnomAD v4.1, supporting that it is not rare enough for PM2.
BP1
Strong
review
Benign
BP1_Strong is met. p.(His114Arg) is a missense variant outside the BRCA2 clinically important functional domains defined by ENIGMA (aa 10-40 and aa 2481-3186), and SpliceAI predicts no significant splice impact (max delta 0.03 ≤0.1).
Protein consequence is p.(His114Arg), residue 114.Clinically important BRCA2 domains for this rule are aa 10-40 and aa 2481-3186.SpliceAI max delta score 0.03.
Assessed · not applied
· 11 not met · 3 not assessed
Pathogenic
PS1
No workspace evidence identified a different nucleotide change with the same amino-acid or same splicing outcome already classified pathogenic/likely pathogenic under BRCA2 ENIGMA rules.
PS3
No calibrated damaging functional result for c.341A>G/p.(His114Arg) was found in ENIGMA BRCA2 Table 9, and the Parsons/ENIGMA multifactorial sheet does not provide damaging functional evidence for this variant.
PS4
No qualifying case-control enrichment was demonstrated.
PM2
Variant is present in gnomAD v2.1 and v4.1, so it is not absent from controls.
PM3
No Fanconi anemia proband/co-occurrence evidence was assembled for this case.
PP1
No segregation LR supporting pathogenicity was assembled.
PP3
PP3 is not met because p.(His114Arg) lies outside BRCA2 clinically important functional domains and SpliceAI is low (max delta 0.03, below the splicing threshold for PP3).
PP4
No multifactorial clinical LR meeting BRCA2 PP4 thresholds was assembled.
Benign
BA1
gnomAD v2.1 grpmax FAF is 7.443e-05, below the BRCA2 BA1 threshold of >0.001.
BS2
No phenotype-resolved biallelic/proband data relevant to BRCA2-related Fanconi anemia were assembled; population homozygotes alone do not establish BS2 under the BRCA2 specification.
BS3
No calibrated benign functional result for c.341A>G/p.(His114Arg) was found in ENIGMA Table 9, and HUMU does not provide qualifying benign functional assay evidence for this variant.
BS4
No quantitative non-segregation LR meeting BS4 thresholds was assembled.
BP4
BP4 is restricted to variants inside BRCA2 clinically important functional domains with no predicted impact; residue 114 is outside those domains, so BP4 is not the correct benign code here.
BP5
No multifactorial LR against pathogenicity meeting BP5 thresholds was assembled.
N/A · 12
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
Allele frequency by ancestry
three datasets · side by side
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