Variant classification summary

NM_007294.3:c.5089T>C

BRCA1 · NP_009225.1:p.(Cys1697Arg) · NM_007294.3

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

Gene: BRCA1 Transcript: NM_007294.3

Final call

Likely Pathogenic

PS3_Strong PM2_Supporting PP3_Supporting PP5_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Cys1697Arg)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.5089T>C (p.Cys1697Arg) variant has not been observed in COSMIC and has been reported in ClinVar, including a pathogenic expert-panel classification from ClinGen ENIGMA.

2

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

3

In calibrated functional studies summarized by the BRCA1 expert-panel resources, this variant showed loss of BRCA1 function, and the expert-panel table assigns PS3_Strong.

4

Computational evidence supports a damaging protein effect because the variant is in the BRCA1 BRCT repeats, BayesDel is 0.398132 (above the PP3 threshold of 0.28), and REVEL is 0.914, while SpliceAI predicts no significant splice effect with a max delta score of 0.08.

Final determination: Likely pathogenic based on PS3_Strong with at least two supporting pathogenic criteria (PM2_Supporting and PP3_Supporting) under ENIGMA Table 3; PP5_Supporting is additional supporting evidence and is not required for the final combination.

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	Not met	This missense variant results in p.(Cys1697Arg) and is not a nonsense, frameshift, initiation-loss, or canonical +/-1,2 splice variant. SpliceAI predicts no significant splice effect (max delta score 0.08), so available evidence does not support a loss-of-function mechanism required for PVS1.	pvs1_gene_context pvs1_variant_assessment cspec spliceai
PS1	Not assessed	No evidence was identified that this variant produces the same pathogenic amino acid or the same pathogenic splicing consequence as a previously established BRCA1 pathogenic variant. PS1 was not applied.	cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	De novo occurrence is not used in this BRCA1 expert-panel framework, so PS2 is not applicable.	cspec
PS3	Met	In calibrated functional studies summarized by the BRCA1 expert-panel specification, this variant showed abnormal protein function consistent with loss of function. Table 9 assigns PS3_Strong for c.5089T>C, and the supplementary functional dataset records complete functional impact/LOF.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4	Not assessed	Although this variant has been reported in affected individuals and is classified as pathogenic by the ClinVar ENIGMA expert panel, no case-control comparison with a significant odds ratio or lower confidence interval excluding 2.0 was identified. PS4 was not applied.	clinvar cspec
PM1	N/A	PM1 is not used in this BRCA1 expert-panel framework for this variant context.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. That absence supports rarity in population controls and is consistent with PM2_Supporting.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified for biallelic BRCA1 disease with a second variant in trans in a patient with a phenotype consistent with BRCA1-related Fanconi anemia. PM3 was not applied.	cspec
PM4	N/A	PM4 is not applicable because this is a missense substitution rather than a protein length-changing in-frame variant or stop-loss event, and the BRCA1 expert-panel framework does not use PM4 here.	cspec
PM5	N/A	The BRCA1 expert-panel PM5 rule available in the reviewed materials is the PTC-specific PM5_PTC framework for qualifying truncating variants. This missense variant does not meet that PM5 context.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Assumed de novo occurrence without confirmed maternity and paternity is not used in this BRCA1 expert-panel framework, 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 this BRCA1 expert-panel framework, so it is not applicable.	cspec
PP3	Met	This missense variant lies within the BRCA1 BRCT repeats, a clinically important functional domain, and computational evidence supports a damaging protein effect. BayesDel is 0.398132, which is above the BRCA1 PP3 threshold of 0.28, REVEL is 0.914, and SpliceAI does not predict a meaningful splice effect (max delta score 0.08). These findings support PP3.	cspec vcep_appendices_v1_2_2024_11_18 bayesdel revel spliceai vcep_supplementarytables_v1_2_2024_11_18
PP4	Not met	In the BRCA1 clinical-history likelihood-ratio table, this variant has an LR of 1.211619929099039 based on 1 proband. This value is below the PP4 threshold of 2.08, so the available clinical-history evidence does not support PP4.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 cspec
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 and therefore does not exceed the BA1 population threshold. BA1 is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the BS1 thresholds. BS1 is not met.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No scored observations of this variant in individuals without features of BRCA1-related Fanconi anemia were identified under the BRCA1 expert-panel BS2 framework. BS2 was not applied.	cspec
BS3	Not met	Available functional evidence does not show normal BRCA1 function. Instead, calibrated studies summarized by the BRCA1 expert-panel resources show loss of function and assign PS3_Strong, so BS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4	Not assessed	No quantitative non-segregation data were identified for this variant, so BS4 was not applied.	cspec
BP1	Not met	This missense variant is located within the BRCA1 BRCT repeats, which are a clinically important functional domain, and computational evidence supports a damaging effect rather than a benign one. BP1 is not met.	cspec vcep_appendices_v1_2_2024_11_18 bayesdel spliceai
BP2	N/A	BP2 is not used in this BRCA1 expert-panel framework, so it is not applicable.	cspec
BP3	N/A	BP3 is not used in this BRCA1 expert-panel framework, so it is not applicable.	cspec
BP4	Not met	This variant does not meet the BRCA1 BP4 rule because it is a missense change within a clinically important domain and BayesDel is 0.398132, which is above the benign BP4 threshold of 0.15. SpliceAI predicts no significant splice effect (max delta score 0.08), but the protein-based prediction does not support BP4.	cspec bayesdel spliceai vcep_appendices_v1_2_2024_11_18
BP5	Not met	In the BRCA1 clinical-history likelihood-ratio table, this variant has an LR of 1.211619929099039 based on 1 proband. This value is above the BP5 threshold of 0.48 and falls in the neutral zone, so BP5 is not met.	vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 cspec
BP6	N/A	BP6 is not used in this BRCA1 expert-panel framework, so it is not applicable.	cspec
BP7	Not met	This is a missense variant within the BRCA1 BRCT repeats. Although SpliceAI predicts no significant splice impact (max delta score 0.08), available evidence does not show normal protein function, and BS3 is not met, so BP7 is not met.	cspec spliceai vcep_specifications_table9_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18

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