Classification rationale

BS1BS3BP1 Benign

BRCA1 c.425C>A

The BRCA1 c.425C>A (p.Pro142His) variant has been reported in ClinVar with an ENIGMA expert panel benign classification.¹ 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).² Calibrated BRCA1 functional evidence supports no damaging effect, with ENIGMA Table 9 assigning BS3_Strong and supplementary functional data describing no functional impact.³ 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 PP3.⁴

BS1 + BS3 + BP1 → Benign

1 clinvar ↗

2 cspec ↗gnomad_v2 ↗gnomad_v4 ↗

3 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_8vcep_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

4 cspec ↗spliceai ↗vcep_a_p_p_e_n_d_i_c_e_s___v_1___2___2_0_2_4___1_1___1_8

Gene diagram · NM_007294.4 · variants mapped to exon structure

BRCA1 NM_007294.4

Fetching transcript structure from UCSC…

Applied criteria · 3 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.63935e-05; MAF= 0.00564%, 91/1613662 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000250142; MAF= 0.02501%, 15/59966 alleles, homozygotes = 0); grpmax FAF= 0.00015364.

v2.1

This variant is present in gnomAD v2.1 (AF= 9.57746e-05; MAF= 0.00958%, 27/281912 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000283752; MAF= 0.02838%, 10/35242 alleles, homozygotes = 0); grpmax FAF= 0.00015726.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0056% · 91 / 1,613,662
0 hom · FAF 0.015%

Admixed American 15 / 59,966	0.025%
Middle Eastern 1 / 6,082	0.016%
Remaining individuals 10 / 62,474	0.016%
European (non-Finnish) 64 / 1,179,892	0.0054%
South Asian 1 / 91,000	0.0011%

+ 5 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0096% · 27 / 281,912
0 hom · FAF 0.016%

Admixed American 10 / 35,242	0.028%
Remaining individuals 2 / 7,192	0.028%
European (non-Finnish) 15 / 128,916	0.012%

+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Likely Neutral

OncoKB classifies this variant as Likely Neutral; biological effect: Likely Neutral.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99070445, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots