The BRCA1 c.5090G>A (p.Cys1697Tyr; C1697Y) variant has been reported in ClinVar as likely pathogenic by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, with additional clinical-laboratory submissions including likely pathogenic, pathogenic, and uncertain significance.1 This variant is absent from the retrieved gnomAD v2.1 and gnomAD v4.1 population datasets, supporting PM2 at Supporting strength and arguing against BA1 or BS1 frequency-based benign evidence.2 Calibrated ENIGMA functional evidence reports BRCA1 c.5090G>A p.(Cys1697Tyr) as PS3 Strong, with supplementary functional data recording complete functional impact and loss-of-function behavior.3 The variant affects residue 1697 within the BRCA1 BRCT repeats, a clinically important domain, has BayesDel no-AF approximately 0.386-0.39 above the ENIGMA PP3 threshold of ≥0.28, and has SpliceAI max delta 0.03 below the predicted splice-impact threshold.4
BRCA1
Final classification
Likely Pathogenic
BRCA1 c.5090G>A · p.Cys1697Tyr
BRCA1
The BRCA1 c.5090G>A (p.Cys1697Tyr; C1697Y) variant has been reported in ClinVar as likely pathogenic by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, with additional clinical-laboratory submissions including likely pathogenic, pathogenic, and uncertain significance.
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 Table 3 adapted ACMG/AMP criteria-combination framework was used. Applied pathogenic evidence comprises 1 Strong criterion (PS3) and 2 Supporting criteria (PM2, PP3), with no benign criteria met.
Classification rationale
PS3PM2PP3
Likely Pathogenic
BRCA1 c.5090G>A
PS3 + PM2 + PP3
→
Likely Pathogenic
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
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_8vcep_a_p_p_e_n_d_i_c_e_s___v_1___2___2_0_2_4___1_1___1_8spliceai ↗cspec ↗
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 pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Pathogenic (3 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
Functional
Likely Oncogenic
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links