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

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

BRCA1 NM_007294.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 13 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

BS1 strong Benign

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.

gnomAD v2.1 grpmax FAF 0.00015726 (>0.0001).gnomAD v4.1 joint grpmax FAF 0.00015364 (>0.0001).

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BS3 strong Benign

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.

ENIGMA Table 9 lists BS3 Strong for c.425C>A.Supplementary functional data list c.425C>A as no functional impact.

BP1 strong Benign

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.

p.Pro142His is outside the BRCA1 clinically important domains defined by ENIGMA.SpliceAI max delta score 0.00 (<=0.1).

cspec ↗spliceai ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PS1 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.

PS3 Available calibrated functional evidence does not support a damaging effect.

PS4 No case-control study or quantitative affected-versus-control comparison meeting the ENIGMA PS4 threshold was identified, so PS4 was not applied.

PM2 This variant is not absent from population databases.

PM3 No evidence of BRCA1-related Fanconi anemia with a qualifying in-trans second BRCA1 variant was identified, so PM3 was not applied.

PP1 No quantitative co-segregation data were identified for this variant, so PP1 was not applied.

PP3 Computational evidence does not meet the ENIGMA PP3 thresholds.

PP4 No multifactorial clinical likelihood ratio meeting the ENIGMA PP4 thresholds was identified, so PP4 was not applied.

Benign

BA1 Population data do not reach the ENIGMA BA1 threshold.

BS2 No point-based BS2 evidence from unaffected individuals without Fanconi anemia features was identified, so BS2 was not applied.

BS4 No quantitative lack-of-segregation dataset was identified for this variant, so BS4 was not applied.

BP5 No multifactorial likelihood ratio against pathogenicity meeting the ENIGMA BP5 thresholds was identified, so BP5 was not applied.

BP7 No RNA study showing a benign transcript effect was identified for this missense variant, so BP7 was not applied.

N/A · 12 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4 · BP6

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

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