NM_007294.4:c.5089T>C

BRCA1 · NP_009225.1:p.(Cys1697Arg) · NM_007294.4

GRCh37: chr17:41215954 A>G · GRCh38: chr17:43063937 A>G

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Pathogenic

PS3_Strong PP3_Supporting PP5_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Cys1697Arg)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA1 c.5089T>C (p.Cys1697Arg) variant has been reported in ClinVar as Pathogenic by the ClinGen ENIGMA expert panel and is listed in OncoKB as Likely Oncogenic with loss-of-function effect.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.

Calibrated BRCA1 functional studies compiled by ENIGMA show complete functional impact/loss of function for p.(Cys1697Arg), supporting PS3_Strong.

The variant lies within the BRCA1 BRCT repeat region, has a BayesDel score of 0.398 which is above the PP3 threshold of 0.28, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.08, supporting PP3.

Final determination: Under the ENIGMA BRCA1/BRCA2 v1.2 Table 3 combining rules, 1 Strong pathogenic criterion with 2 Supporting pathogenic criteria meets Likely Pathogenic.

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 is a missense variant, not a null variant or canonical ±1/2 splice variant, so the BRCA1 ENIGMA PVS1 rule does not apply.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No previously classified pathogenic variant with the same amino acid substitution was identified in the reviewed evidence, so PS1 was not applied.	cspec clinvar
PS2	N/A	De novo evidence is not used for BRCA1 in this specification, so PS2 is not applicable.	cspec
PS3	Met	Calibrated BRCA1 functional studies show this variant has damaging loss-of-function effects. ENIGMA Table 9 assigns PS3_Strong to c.5089T>C based on three studies, and supplementary functional tables classify p.(Cys1697Arg) as having complete functional impact/loss of function.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4	Not assessed	The reviewed evidence does not provide a case-control analysis with p-value ≤0.05 and odds ratio ≥4 with the lower confidence interval excluding 2.0, so PS4 was not applied.	cspec clinvar
PM1	N/A	Although this variant lies in the BRCA1 BRCT region, PM1 is not used in the ENIGMA BRCA1 specification.	cspec vcep_appendices_v1_2_2024_11_18
PM2	Not assessed	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with rarity, but the ENIGMA PM2 rule specifically requires absence in gnomAD v2.1 and v3.1 with average read depth ≥25, and those full coverage elements were not provided here.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified for biallelic BRCA1 disease or Fanconi anemia probands with qualifying co-occurring BRCA1 variants, so PM3 was not applied.	cspec
PM4	N/A	PM4 does not apply because this is not a protein length-changing variant, and the BRCA1 ENIGMA specification marks PM4 as not applicable.	cspec
PM5	N/A	In the BRCA1 ENIGMA specification, PM5 is used for protein-terminating variants in eligible exons. This variant is missense, so PM5 does not apply.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Assumed de novo evidence is not used for BRCA1 in this specification, so PM6 is not applicable.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 was not applied.	cspec
PP2	N/A	PP2 is not used in the BRCA1 ENIGMA specification.	cspec
PP3	Met	This missense variant is located in the BRCA1 BRCT repeats (amino acids 1650-1857), has a BayesDel score of 0.398, which is above the ENIGMA PP3 threshold of 0.28, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.08. These findings support a damaging protein effect consistent with PP3.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP4	Not met	The BRCA1 clinical-history likelihood ratio for this variant is 1.21 in 1 proband, which is below the ENIGMA PP4 threshold of 2.08, so PP4 is not met.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the BA1 threshold of filter allele frequency greater than 0.1%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the BS1 thresholds of filter allele frequency above 0.002% or 0.01%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No qualifying point-based evidence was identified from individuals without Fanconi anemia features, so BS2 was not applied.	cspec
BS3	Not met	Available calibrated functional studies do not show a neutral effect. Instead, ENIGMA Table 9 and the supplementary functional dataset classify this variant as damaging with complete functional impact/loss of function, so BS3 is not met.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	No quantitative evidence for lack of segregation was identified, so BS4 was not applied.	cspec
BP1	Not met	This missense variant is located within the BRCA1 BRCT repeats rather than outside a clinically important domain, and the BayesDel score is 0.398, which does not support a benign protein prediction. Therefore BP1 is not met.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP2	N/A	BP2 is not used in the BRCA1 ENIGMA specification.	cspec
BP3	N/A	BP3 is not used in the BRCA1 ENIGMA specification.	cspec
BP4	Not met	Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, the BayesDel score is 0.398, which is above the benign threshold of 0.15. Because BP4 for missense variants in clinically important domains requires BayesDel ≤0.15 and SpliceAI ≤0.1, BP4 is not met.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP5	Not met	The BRCA1 clinical-history likelihood ratio for this variant is 1.21 in 1 proband, which is above the ENIGMA BP5 threshold of 0.48 and falls in the neutral zone, so BP5 is not met.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is not used in the BRCA1 ENIGMA specification.	cspec
BP7	N/A	This is a missense variant rather than a silent or intronic variant in the ENIGMA BP7 categories, so BP7 does not apply.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.