Variant classification summary

NM_007294.4:c.5090G>A

BRCA1 · NP_009225.1:p.(Cys1697Tyr) · NM_007294.4

GRCh37: chr17:41215953 C>T · GRCh38: chr17:43063936 C>T

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Pathogenic

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Cys1697Tyr)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

Final determination: The ENIGMA BRCA1/2 Table 3 framework classifies a variant as likely pathogenic when 1 Strong pathogenic criterion and at least 2 Supporting pathogenic criteria are met; this variant meets PS3_Strong, PM2_Supporting, and PP3_Supporting.

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 variant is a missense substitution, NP_009225.1:p.(Cys1697Tyr), rather than a nonsense, frameshift, canonical ±1/2 splice, initiation-codon, or exon-level deletion variant. Although BRCA1 loss of function is an established disease mechanism, PVS1 is not applicable to this missense change under the ENIGMA BRCA1/2 specification.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	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. PS1 was therefore not applied.	cspec clinvar
PS2	N/A	The ENIGMA BRCA1/2 specification does not use de novo evidence for BRCA1/2-related cancers because these cancers are relatively common and de novo predictive value is not calibrated. PS2 is not applicable.	cspec
PS3	Met	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.	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 cspec
PS4	Not assessed	No case-control dataset with p-value ≤0.05, odds ratio ≥4, and lower confidence interval excluding 2.0 was identified for this variant. PS4 was not applied.	cspec clinvar
PM1	N/A	Although p.Cys1697Tyr lies within the clinically important BRCA1 BRCT repeat region, the ENIGMA BRCA1/2 specification treats domain/location information as part of the PP3/BP4 bioinformatic framework rather than applying PM1 as a separate criterion. PM1 is not applicable.	cspec vcep_a_p_p_e_n_d_i_c_e_s___v_1___2___2_0_2_4___1_1___1_8
PM2	Met	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 gnomad_v4 cspec
PM3	Not assessed	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. PM3 was not applied.	cspec
PM4	N/A	This variant is a single amino-acid substitution and does not alter protein length. The ENIGMA BRCA1/2 specification also treats PM4 as not applicable, with protein-change context handled through the bioinformatic framework. PM4 is not applicable.	cspec
PM5	N/A	The ENIGMA BRCA1/2 PM5 criterion is specified for protein termination codon variants used with PVS1, not for this missense substitution. PM5_PTC is therefore not applicable.	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 BRCA1/2 specification does not use assumed de novo evidence for BRCA1/2-related cancers. PM6 is not applicable.	cspec
PP1	Not assessed	No quantitative co-segregation analysis or family segregation likelihood ratio was identified for this variant. PP1 was not applied.	cspec
PP2	N/A	The ENIGMA BRCA1/2 specification marks PP2 as not applicable because BRCA1 has a high frequency of benign missense variation. PP2 is not applicable.	cspec
PP3	Met	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.	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 spliceai cspec 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 likelihood ratio based on clinical features, family history, tumor pathology, co-occurrence, or related calibrated clinical data was identified. PP4 was not applied.	cspec
PP5	N/A	Although ClinVar includes an ENIGMA expert-panel likely pathogenic assertion for this variant, the ENIGMA BRCA1/2 specification states that PP5 is not used. PP5 is not applicable.	cspec clinvar
BA1	Not met	This variant is absent from the retrieved gnomAD v2.1 and v4.1 datasets, with observed frequency 0. This is below, not above, the ENIGMA BA1 threshold of FAF >0.1% (>0.001), so BA1 is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from the retrieved gnomAD v2.1 and v4.1 datasets, with observed frequency 0. This is below the ENIGMA BS1 thresholds of FAF >0.002% for Supporting or >0.01% for Strong, so BS1 is not met.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No evidence was identified that this variant was observed in unaffected adults or in contexts supporting the ENIGMA BS2 point framework. BS2 was not applied.	cspec
BS3	Not met	Available calibrated functional evidence supports damaging protein effect rather than normal function. Therefore benign functional evidence criterion BS3 is not met.	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 cspec
BS4	Not assessed	No quantitative evidence of lack of segregation in affected family members was identified. BS4 was not applied.	cspec
BP1	Not met	This variant is a missense substitution within the BRCA1 BRCT repeat region, which is a clinically important functional domain. BP1_Strong requires a missense, synonymous, or in-frame variant outside a clinically important functional domain with SpliceAI ≤0.1; because p.Cys1697Tyr is inside the BRCT domain, BP1 is not met.	cspec vcep_a_p_p_e_n_d_i_c_e_s___v_1___2___2_0_2_4___1_1___1_8 spliceai
BP2	N/A	The ENIGMA BRCA1/2 specification applies BP2 only in the context of BS2, and no BS2 evidence was identified. BP2 is not applicable.	cspec
BP3	N/A	This variant is not an in-frame deletion or insertion in a repetitive region, and the ENIGMA BRCA1/2 specification marks BP3 as not applicable. BP3 is not applicable.	cspec
BP4	Not met	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. Although SpliceAI max delta score is 0.03 and therefore below the no-splice-impact threshold of ≤0.1, the protein-impact prediction does not support BP4. BP4 is not met.	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 spliceai cspec
BP5	Not assessed	No calibrated multifactorial likelihood ratio against pathogenicity was identified for this variant. BP5 was not applied.	cspec
BP6	N/A	The ENIGMA BRCA1/2 specification states that BP6 is not used. BP6 is not applicable.	cspec
BP7	N/A	This variant is a missense substitution within a clinically important BRCA1 functional domain. BP7 is intended for qualifying benign mRNA-only evidence in intronic, synonymous, or missense/in-frame variants outside clinically important domains, or for domain missense variants only when BS3 is also met; BS3 is not met. BP7 is therefore not applicable.	cspec spliceai

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