Variant classification summary

NM_007294.4:c.425C>A

BRCA1 · NP_009225.1:p.(Pro142His) · NM_007294.4

GRCh37: chr17:41256155 G>T · GRCh38: chr17:43104138 G>T

Gene: BRCA1 Transcript: NM_007294.4

Final call

Benign

BS1_Strong BS3_Strong BP1_Strong

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Pro142His)

gnomAD AF

ClinVar

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.425C>A (p.Pro142His) variant has been reported in ClinVar with an ENIGMA expert panel benign classification.

2

This variant is present in gnomAD, and the highest observed filter allele frequencies exceed the ENIGMA BS1_Strong threshold of 0.0001 (gnomAD v2.1 grpmax FAF 0.00015726; gnomAD v4.1 joint grpmax FAF 0.00015364).

3

Calibrated BRCA1 functional evidence supports no damaging effect, with ENIGMA Table 9 assigning BS3_Strong and supplementary functional data describing no functional impact.

4

This missense change is outside the BRCA1 clinically important functional domains, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, which is consistent with BP1_Strong and does not support PP3.

Final determination: ENIGMA Table 3 supports a Benign classification because at least two strong benign criteria are met.

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	This is a missense variant, not a nonsense, frameshift, canonical ±1/2 splice, initiation-codon, or exon-level loss-of-function variant, so PVS1 does not apply.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No previously classified pathogenic or likely pathogenic variant with the same predicted amino acid change or the same predicted splice effect was identified in the reviewed sources, so PS1 was not applied.	cspec clinvar
PS2	N/A	The ENIGMA BRCA1 specification does not use PS2 for this VCEP framework.	cspec
PS3	Not met	Available calibrated functional evidence does not support a damaging effect. ENIGMA Table 9 assigns BS3_Strong for this variant, and supplementary functional data describe no functional impact rather than loss of function.	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_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
PS4	Not assessed	No case-control study or quantitative affected-versus-control comparison meeting the ENIGMA PS4 threshold was identified, so PS4 was not applied.	cspec clinvar
PM1	N/A	PM1 is not used in the ENIGMA BRCA1 specification.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.0000958 (27/281912) and in gnomAD v4.1 at AF 0.0000564 (91/1613662), so the ENIGMA PM2 absence criterion is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence of BRCA1-related Fanconi anemia with a qualifying in-trans second BRCA1 variant was identified, so PM3 was not applied.	cspec
PM4	N/A	PM4 is not used in the ENIGMA BRCA1 specification.	cspec
PM5	N/A	In the ENIGMA BRCA1 framework, PM5 is used for protein-truncating variants already annotated with PVS1. This missense variant does not meet that context, so PM5 does not apply.	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 ENIGMA BRCA1 specification does not use PM6 for this VCEP framework.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 was not applied.	cspec clinvar
PP2	N/A	PP2 is not used in the ENIGMA BRCA1 specification.	cspec
PP3	Not met	Computational evidence does not meet the ENIGMA PP3 thresholds. SpliceAI predicts no splice effect with a maximum delta score of 0.00, which is below the ≥0.2 splicing threshold, and the variant lies outside the BRCA1 clinically important functional domains required for missense PP3 application.	cspec spliceai vcep_a_p_p_e_n_d_i_c_e_s___v_1___2___2_0_2_4___1_1___1_8
PP4	Not assessed	No multifactorial clinical likelihood ratio meeting the ENIGMA PP4 thresholds was identified, so PP4 was not applied.	cspec
PP5	N/A	PP5 is not used in the ENIGMA BRCA1 specification.	cspec
BA1	Not met	Population data do not reach the ENIGMA BA1 threshold. The highest observed filter allele frequencies are 0.00015726 in gnomAD v2.1 and 0.00015364 in gnomAD v4.1, both below the BA1 cutoff of >0.001.	cspec gnomad_v2 gnomad_v4
BS1	Met	This variant exceeds the ENIGMA BS1 threshold for benign population frequency. The highest observed filter allele frequency is 0.00015726 in gnomAD v2.1 and 0.00015364 in gnomAD v4.1, both above the BS1_Strong cutoff of >0.0001.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No point-based BS2 evidence from unaffected individuals without Fanconi anemia features was identified, so BS2 was not applied.	cspec
BS3	Met	Calibrated functional evidence supports no damaging effect. ENIGMA Table 9 assigns BS3_Strong to BRCA1 c.425C>A (p.Pro142His), and supplementary functional data describe this variant as having no functional impact.	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_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
BS4	Not assessed	No quantitative lack-of-segregation dataset was identified for this variant, so BS4 was not applied.	cspec
BP1	Met	This missense variant is outside the BRCA1 clinically important functional domains and has no predicted splice effect. p.Pro142His is outside the RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains, and SpliceAI shows a maximum delta score of 0.00, which is below the ≤0.1 threshold; this supports BP1_Strong.	cspec spliceai vcep_a_p_p_e_n_d_i_c_e_s___v_1___2___2_0_2_4___1_1___1_8
BP2	N/A	BP2 is not used in the ENIGMA BRCA1 specification.	cspec
BP3	N/A	BP3 is not used in the ENIGMA BRCA1 specification.	cspec
BP4	N/A	For BRCA1 missense variants, BP4 is reserved for variants inside a clinically important functional domain with BayesDel no-AF ≤0.15 and SpliceAI ≤0.1. p.Pro142His is outside those domains, so BP4 does not apply in this framework.	cspec vcep_a_p_p_e_n_d_i_c_e_s___v_1___2___2_0_2_4___1_1___1_8
BP5	Not assessed	No multifactorial likelihood ratio against pathogenicity meeting the ENIGMA BP5 thresholds was identified, so BP5 was not applied.	cspec
BP6	N/A	The ENIGMA BRCA1 specification does not use BP6 for this VCEP framework.	cspec
BP7	Not assessed	No RNA study showing a benign transcript effect was identified for this missense variant, so BP7 was not applied.	cspec spliceai

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