Variant classification summary

NM_000059.4:c.4071A>C

BRCA2 · NP_000050.3:p.(Leu1357=) · NM_000059.4

GRCh37: chr13:32912563 A>C · GRCh38: chr13:32338426 A>C

Gene: BRCA2 Transcript: NM_000059.4

Final call

Benign

BA1 BS1 BP1

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Leu1357=)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BRCA2 ENIGMA BA1 is met because the variant exceeds the stand-alone benign frequency threshold in gnomAD: v2.1 grpmax FAF 0.00161392 and v4.1 grpmax FAF 0.00154091, both >0.001.

2

The variant is synonymous, p.(Leu1357=), and lies outside the BRCA2 clinically important domains defined by ENIGMA; with SpliceAI max delta score 0.00, this satisfies BP1_Strong.

3

ClinVar shows a concordant benign expert-panel assertion from ENIGMA, which supports but does not replace the VCEP rule-based 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 exonic variant p.(Leu1357=) is not a null/splice-donor/acceptor +/-1,2 variant and there is no RNA evidence showing a loss-of-function transcript effect.	cspec spliceai
PS1	N/A	No evidence that this synonymous change has the same proven pathogenic splicing consequence as another pathogenic variant, and the missense-based PS1 rule does not apply.	cspec spliceai
PS2	N/A	Marked not applicable in the BRCA2 ENIGMA specification for this framework.	cspec
PS3	Not assessed	No calibrated functional assay evidence for this specific variant was identified in the reviewed workspace or VCEP 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
PS4	Not assessed	No qualifying case-control enrichment or ENIGMA quantitative pathogenic likelihood evidence for this specific variant was identified in the reviewed workspace/VCEP files.	cspec 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	PM1 is marked not applicable in BRCA2 ENIGMA and this synonymous variant is outside the clinically important domains noted for bioinformatic missense evaluation.	cspec
PM2	Not met	The variant is not absent from controls; it is observed repeatedly in gnomAD v2.1 and v4.1.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No Fanconi-anemia-related biallelic case evidence or phase data were identified.	cspec
PM4	N/A	Marked not applicable in the BRCA2 ENIGMA specification.	cspec
PM5	N/A	This is not a protein-terminating variant and not a qualifying missense substitution for PM5/PM5_PTC.	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	Marked not applicable in the BRCA2 ENIGMA specification.	cspec
PP1	Not assessed	No quantitative segregation data were identified for this case.	cspec
PP2	N/A	Marked not applicable in the BRCA2 ENIGMA specification.	cspec
PP3	Not met	SpliceAI max delta score is 0.00, far below the BRCA2 ENIGMA PP3 splicing threshold of >=0.2; the variant is synonymous, not a missense/in-frame protein-altering change.	spliceai cspec
PP4	Not assessed	No multifactorial clinical LR supporting pathogenicity was identified for this specific variant.	cspec
PP5	N/A	Marked not applicable in the BRCA2 ENIGMA specification.	cspec
BA1	Met	BA1 is met because the variant exceeds the BRCA2 ENIGMA BA1 filter allele frequency threshold (>0.001) in non-founder population data. In gnomAD v2.1 the grpmax FAF is 0.00161392, and in gnomAD v4.1 the grpmax FAF is 0.00154091, both above the stand-alone benign threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Met	BS1 is also met because the variant's gnomAD filter allele frequency is well above the BRCA2 ENIGMA BS1 strong threshold (>0.0001). This is redundant once BA1 is met but remains concordant benign evidence.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No point-based adult observation data without Fanconi anemia features were assembled for this case.	cspec
BS3	Not assessed	No calibrated benign functional assay result for this specific variant was identified.	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 assessed	No quantitative non-segregation likelihood ratio was identified for this variant.	cspec 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
BP1	Met	BP1_Strong is met under BRCA2 ENIGMA because this is a silent substitution, p.(Leu1357=), outside the BRCA2 clinically important domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186), and SpliceAI predicts no splice impact (max delta score 0.00, <=0.1).	cspec spliceai
BP2	N/A	Marked not applicable in the BRCA2 ENIGMA specification.	cspec
BP3	N/A	Marked not applicable in the BRCA2 ENIGMA specification.	cspec
BP4	N/A	For BRCA2 ENIGMA, BP4 silent-variant use is defined for silent variants inside clinically important domains with no splice impact. This variant is outside those domains, so BP1_Strong rather than BP4 is the relevant benign bioinformatic code.	cspec spliceai
BP5	Not assessed	No quantitative multifactorial likelihood ratio against pathogenicity was assembled for this variant.	cspec
BP6	N/A	Marked not applicable in the BRCA2 ENIGMA specification; external assertions such as ClinVar are not used as BP6 in this framework.	cspec clinvar
BP7	Not assessed	No qualifying RNA assay evidence was identified. Computational splice neutrality alone does not satisfy the BRCA2 ENIGMA BP7 RNA rule, and the BP7 supporting silent-variant rule is for silent variants inside clinically important domains if BP4 is met.	cspec spliceai

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