LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-12
Case ID: NM_000059.4_c.341A_G_20260412_232204
Framework: ACMG/AMP 2015
Variant classification summary

NM_000059.4:c.341A>G

BRCA2  · NP_000050.3:p.(His114Arg)  · NM_000059.4
GRCh37: chr13:32899237 A>G  ·  GRCh38: chr13:32325100 A>G
Gene: BRCA2 Transcript: NM_000059.4
Final call
BP1_Strong BS1_Supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(His114Arg)
gnomAD AF
ClinVar
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The variant is BRCA2 NM_000059.4:c.341A>G, p.(His114Arg), a missense substitution at residue 114.
2
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).
3
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).
4
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.
5
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.
6
Overall, the assembled workspace supports a benign-leaning VCEP classification without conflicting pathogenic evidence sufficient to retain VUS; the best fit is Likely benign.
Final determination:
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Missense variant p.(His114Arg); BRCA2 PVS1 rules apply to null variants or RNA-only evidence causing loss of function, which is not the case here.
cspec 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
PS1 Not assessed 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.
cspec 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
PS2 N/A BRCA2 ENIGMA marks PS2 as not applicable.
cspec
PS3 Not met 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.
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 vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
PS4 Not met No qualifying case-control enrichment was demonstrated. In the ENIGMA multifactorial dataset, c.341A>G has no case-control LR populated and the combined LR is 0.5897487000827281, which does not support pathogenic enrichment.
vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1 vcep_s_u_p_p_l_e_m_e_n_t_a_r_y_t_a_b_l_e_s___v_1___2___2_0_2_4___1_1___1_8 cspec
PM1 N/A BRCA2 ENIGMA marks PM1 as not applicable; domain/location information is instead incorporated into the BRCA-specific BP1/BP4/PP3 framework.
cspec 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
PM2 Not met Variant is present in gnomAD v2.1 and v4.1, so it is not absent from controls.
gnomad_v2 gnomad_v4 cspec
PM3 Not assessed No Fanconi anemia proband/co-occurrence evidence was assembled for this case.
cspec
PM4 N/A BRCA2 ENIGMA marks PM4 as not applicable.
cspec
PM5 N/A BRCA2 PM5 in this specification is for PTC variants in eligible exons; this variant is missense.
cspec vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_4___v_1___2___2_0_2_4___1_1___1_8
PM6 N/A BRCA2 ENIGMA marks PM6 as not applicable.
cspec
PP1 Not met No segregation LR supporting pathogenicity was assembled. Parsons/ENIGMA does not show a segregation LR for this variant.
vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1 cspec
PP2 N/A BRCA2 ENIGMA marks PP2 as not applicable.
cspec
PP3 Not met 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).
cspec spliceai 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
PP4 Not met No multifactorial clinical LR meeting BRCA2 PP4 thresholds was assembled. Parsons/ENIGMA combined LR is 0.5897487000827281, below the pathogenic PP4 threshold.
vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1 cspec
PP5 N/A BRCA2 ENIGMA marks PP5 as not applicable.
cspec
BA1 Not met gnomAD v2.1 grpmax FAF is 7.443e-05, below the BRCA2 BA1 threshold of >0.001.
gnomad_v2 cspec
BS1 Met BRCA2 BS1_Supporting is met because gnomAD v2.1 grpmax FAF is 7.443e-05, which is >0.00002 and ≤0.0001.
gnomad_v2 cspec
BS2 Not assessed 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.
cspec gnomad_v2 gnomad_v4
BS3 Not met 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.
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 vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
BS4 Not met No quantitative non-segregation LR meeting BS4 thresholds was assembled. Parsons/ENIGMA shows no segregation LR for this variant, and combined LR is not low enough for BS4.
vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1 cspec
BP1 Met 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).
cspec spliceai 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
BP2 N/A BRCA2 ENIGMA marks BP2 as not applicable except within BS2 context, which is not established here.
cspec
BP3 N/A BRCA2 ENIGMA marks BP3 as not applicable.
cspec
BP4 Not met 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.
cspec spliceai
BP5 Not met No multifactorial LR against pathogenicity meeting BP5 thresholds was assembled. Parsons/ENIGMA combined LR is 0.5897487000827281, which is above the BP5 threshold range.
vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1 cspec
BP6 N/A BRCA2 ENIGMA marks BP6 as not applicable.
cspec
BP7 N/A BP7 is for silent/intronic or RNA-only benign evidence contexts; this variant is missense.
cspec spliceai
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