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
Final classification
Likely Pathogenic
PS3PM2PP3
BRCA1
c.5090G>A
p.Cys1697Tyr
This variant
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 ↗
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
PS3
strong
Pathogenic
This BRCA1 missense variant has calibrated functional evidence showing damaging protein effect. ENIGMA Table 9 lists c.5090G>A p.(Cys1697Tyr) as PS3 Strong, with two calibrated studies reporting protein function similar to pathogenic controls; the supplementary functional dataset also records a complete functional impact/loss-of-function result. This supports PS3 at Strong strength.
ENIGMA Table 9: BRCA1 c.5090G>A p.(Cys1697Tyr)PS3 Strongtwo calibrated studies
PM2
supporting
Pathogenic
This variant is absent from the retrieved gnomAD v2.1 and gnomAD v4.1 datasets, corresponding to observed allele frequency 0 in both datasets. This is below the ENIGMA absence/rarity requirement for PM2_Supporting and supports PM2 at Supporting strength, assuming adequate local coverage.
gnomAD v2.1: absentgnomAD v4.1: absent.
PP3
supporting
Pathogenic
This variant is a missense substitution within the BRCA1 BRCT repeat domain, a clinically important functional domain spanning amino acids 1650-1857. The bioinformatic dataset reports BayesDel no-AF approximately 0.386-0.39, which is above the ENIGMA PP3 threshold of ≥0.28, and SpliceAI max delta score is 0.03, below the splice-impact threshold of ≥0.2. These findings support a deleterious protein effect without predicted splicing impact, meeting PP3 at Supporting strength.
Supplementary bioinformatic tables: c.5090G>A p.Cys1697Tyr in BRCT repeatsBayesDel no-AF 0.386406/0.39SpliceAI max delta 0.03.
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
PS1
No independent evidence was identified that a different nucleotide change produces the same p.(Cys1697Tyr) amino acid change and has been classified as pathogenic by the ENIGMA specification.
PS4
No case-control dataset with p-value ≤0.05, odds ratio ≥4, and lower confidence interval excluding 2.0 was identified for this variant.
PM3
No evidence was identified that this variant occurs in trans with a pathogenic BRCA1 variant in an individual with a BRCA1/2-related Fanconi anemia phenotype.
PP1
No quantitative co-segregation analysis or family segregation likelihood ratio was identified for this variant.
PP4
No multifactorial likelihood ratio based on clinical features, family history, tumor pathology, co-occurrence, or related calibrated clinical data was identified.
Benign
BA1
This variant is absent from the retrieved gnomAD v2.1 and v4.1 datasets, with observed frequency 0.
BS1
This variant is absent from the retrieved gnomAD v2.1 and v4.1 datasets, with observed frequency 0.
BS2
No evidence was identified that this variant was observed in unaffected adults or in contexts supporting the ENIGMA BS2 point framework.
BS3
Available calibrated functional evidence supports damaging protein effect rather than normal function.
BS4
No quantitative evidence of lack of segregation in affected family members was identified.
BP1
This variant is a missense substitution within the BRCA1 BRCT repeat region, which is a clinically important functional domain.
BP4
This variant is inside a clinically important BRCA1 functional domain and has BayesDel no-AF approximately 0.386-0.39, which is above the benign BP4 threshold of ≤0.15.
BP5
No calibrated multifactorial likelihood ratio against pathogenicity was identified for this variant.
N/A · 12
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7
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