Variant classification summary

NM_000059.4:c.3111A>G

BRCA2 · NP_000050.3:p.(Gln1037=) · NM_000059.4

GRCh37: chr13:32911603 A>G · GRCh38: chr13:32337466 A>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

BP1_Strong

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Gln1037=)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

2

Q1037 is outside the BRCA2 clinically important domains defined by the specification (PALB2-binding aa 10-40 and DNA-binding aa 2481-3186).

3

SpliceAI predicts no significant splice impact for this variant, with max delta score 0.00, satisfying the no-splicing-predicted part of BP1_Strong.

4

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.

5

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.

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	Synonymous exon 11 variant p.(Gln1037=)/p.(Q1037=) with no evidence in the workspace for an RNA assay showing loss-of-function transcript impact; BRCA2 PVS1 is for null variants or qualifying mRNA assay evidence.	cspec spliceai
PS1	Not met	No same-amino-acid pathogenic comparator or same predicted splice consequence pathogenic comparator was identified in the reviewed workspace materials.	clinvar cspec
PS2	N/A	No de novo case data are present, and the BRCA2 specification marks PS2 as not applicable.	cspec
PS3	Not met	No variant-specific damaging functional assay assignment was identified in Specifications Table 9 or other reviewed VCEP materials.	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
PS4	Not met	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.	clinvar 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
PM1	N/A	The BRCA2 VCEP marks PM1 as not applicable in this specification.	cspec
PM2	Not met	PM2_Supporting requires absence from gnomAD controls. This variant is present in both gnomAD v2.1 and v4.1, so PM2 is not met.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	No Fanconi anemia phenotype or in-trans co-occurrence evidence is present in the workspace.	cspec
PM4	N/A	The BRCA2 VCEP marks PM4 as not applicable.	cspec
PM5	N/A	This is not a protein-terminating variant and not a missense substitution requiring PM5 logic.	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	The BRCA2 VCEP marks PM6 as not applicable.	cspec
PP1	Not met	No quantitative segregation data were present in the workspace.	cspec
PP2	N/A	The BRCA2 VCEP marks PP2 as not applicable.	cspec
PP3	Not met	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.	spliceai cspec
PP4	Not met	No multifactorial likelihood clinical data supporting phenotype-specific enrichment were present in the workspace.	cspec
PP5	N/A	The BRCA2 VCEP marks PP5 as not applicable.	cspec
BA1	Not met	The observed population frequency is far below the BRCA2 BA1 threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	The observed population frequency is below both BRCA2 BS1 thresholds.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	No adult biallelic or phenotype-negative observational dataset relevant to BRCA2 BS2 was present in the workspace.	cspec
BS3	Not met	No variant-specific benign protein functional assay assignment was identified in the reviewed BRCA2 functional table.	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
BS4	Not met	No quantitative lack-of-segregation evidence was present in the workspace.	cspec
BP1	Met	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.	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	The BRCA2 VCEP marks BP2 as not applicable except in the BS2 context, and no such evidence is present.	cspec
BP3	N/A	The BRCA2 VCEP marks BP3 as not applicable.	cspec
BP4	Not met	For silent variants, BRCA2 BP4 applies only inside a clinically important functional domain with no predicted splice impact. This synonymous variant is outside those domains, so BP4 is not the correct benign bioinformatic code.	cspec spliceai
BP5	Not met	No multifactorial likelihood clinical data arguing against pathogenicity were assembled for this specific variant.	cspec
BP6	N/A	The BRCA2 VCEP marks BP6 as not applicable.	cspec
BP7	Not met	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. This variant is outside the defined domains and no RNA assay was identified, so BP7 is not met.	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

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.