Variant classification summary

NM_007294.4:c.3271C>G

BRCA1 · NP_009225.1:p.(Pro1091Ala) · NM_007294.4

GRCh37: chr17:41244277 G>C · GRCh38: chr17:43092260 G>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

BP1_Strong

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Pro1091Ala)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.3271C>G (p.Pro1091Ala; p.P1091A) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, supporting rarity, although the ENIGMA BRCA1 PM2_Supporting rule was not applied because the required specified-control-set and coverage documentation were not identified here.

3

SpliceAI predicts no significant splice effect (maximum delta score 0.01, below the ENIGMA 0.1 and 0.2 splice thresholds); BayesDel no-AF is -0.072 and REVEL is 0.572, and because p.Pro1091Ala lies outside the BRCA1 RING, coiled-coil, and BRCT domains, the ENIGMA BRCA1 missense rules support BP1_Strong and do not support PP3.

Final determination: BP1_Strong is present, but no additional benign criterion is met; under ENIGMA Table 3, a single strong benign criterion alone does not reach a Likely Benign or Benign classification, so the variant remains Uncertain Significance.

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 is a missense variant, not a nonsense, frameshift, initiation-codon, deletion, or canonical ±1,2 splice variant, so it does not meet the BRCA1 ENIGMA or generic null-variant requirements for PVS1.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No previously classified pathogenic or likely pathogenic variant with the same amino acid change or the same predicted splicing effect was identified in the reviewed ClinVar or BRCA1 ENIGMA materials, so PS1 was not applied.	clinvar cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	The BRCA1 ENIGMA specification marks PS2 as not applicable.	cspec
PS3	Not assessed	No variant-specific calibrated functional study assigning PS3 was identified for this variant in the reviewed BRCA1 ENIGMA functional tables, and no variant-specific reviewed functional evidence was identified in OncoKB.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 oncokb
PS4	Not assessed	No case-control dataset or other quantitative prevalence evidence showing enrichment of this variant in affected individuals versus controls was identified, so PS4 was not applied.	cspec clinvar PMID:25394175
PM1	N/A	The BRCA1 ENIGMA specification marks PM1 as not applicable.	cspec
PM2	Not assessed	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which supports rarity; however, the ENIGMA BRCA1 PM2_Supporting rule specifically requires absence in the specified control datasets together with average read depth ≥25, and the required v3.1/depth documentation was not identified here, so PM2 was not applied.	cspec gnomad_v2 gnomad_v4 gnomad_canada vcep_supplementarytables_v1_2_2024_11_18
PM3	Not assessed	No evidence was identified showing this variant in trans with another BRCA1 variant in an individual with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 was not applied.	cspec
PM4	N/A	The BRCA1 ENIGMA specification marks PM4 as not applicable.	cspec
PM5	N/A	In the BRCA1 ENIGMA specification, PM5 is repurposed for protein-truncating variants in eligible exons rather than classic same-residue missense logic. This missense variant is therefore not eligible for PM5.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	The BRCA1 ENIGMA specification marks PM6 as not applicable.	cspec
PP1	Not assessed	No quantitative co-segregation evidence was identified for this variant, so PP1 was not applied.	cspec
PP2	N/A	The BRCA1 ENIGMA specification marks PP2 as not applicable.	cspec
PP3	Not met	SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, which is below the ENIGMA splicing threshold of 0.2 for PP3. BayesDel no-AF is -0.072, which is below the ENIGMA missense PP3 threshold of 0.28, and p.Pro1091Ala lies outside the BRCA1 RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains. REVEL 0.572 was reviewed, but ENIGMA BRCA1 uses BayesDel and domain context for this missense rule. PP3 is therefore not met.	cspec spliceai bayesdel revel vcep_appendices_v1_2_2024_11_18
PP4	Not assessed	No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified in the reviewed BRCA1 clinical-history resources, so PP4 was not applied.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 PMID:17924331
PP5	N/A	The BRCA1 ENIGMA specification marks PP5 as not applicable.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the ENIGMA BA1 filter allele frequency threshold of greater than 0.1% (FAF >0.001).	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the ENIGMA BS1 thresholds of greater than 0.002% or greater than 0.01% filter allele frequency.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No proband-level evidence was identified showing this variant in individuals without features of BRCA1-related Fanconi anemia under the ENIGMA point-based BS2 framework, so BS2 was not applied.	cspec
BS3	Not assessed	No variant-specific calibrated functional study assigning BS3 was identified for this variant in the reviewed BRCA1 ENIGMA functional tables, so BS3 was not applied.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 oncokb
BS4	Not assessed	No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not applied.	cspec PMID:17924331
BP1	Met	This missense variant occurs at p.Pro1091Ala, outside the BRCA1 clinically important domains defined by ENIGMA (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the BP1 threshold of 0.1. These findings meet BP1_Strong.	cspec spliceai vcep_appendices_v1_2_2024_11_18
BP2	N/A	The BRCA1 ENIGMA specification marks BP2 as not applicable.	cspec
BP3	N/A	The BRCA1 ENIGMA specification marks BP3 as not applicable.	cspec
BP4	Not met	SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, and BayesDel no-AF is -0.072, which is below the ENIGMA benign missense threshold of 0.15. However, ENIGMA BRCA1 BP4 for missense variants is restricted to variants inside a clinically important functional domain, and p.Pro1091Ala lies outside the BRCA1 RING, coiled-coil, and BRCT domains. REVEL 0.572 was reviewed, but ENIGMA BRCA1 uses BayesDel and domain context for this rule. BP4 is therefore not met.	cspec spliceai bayesdel revel vcep_appendices_v1_2_2024_11_18
BP5	Not assessed	No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA BP5 thresholds against pathogenicity was identified in the reviewed BRCA1 clinical-history resources, so BP5 was not applied.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 PMID:17924331
BP6	N/A	The BRCA1 ENIGMA specification marks BP6 as not applicable.	cspec
BP7	Not assessed	This is a missense variant. ENIGMA BRCA1 BP7 for missense variants outside a clinically important domain requires mRNA evidence showing no damaging splice effect, and no such RNA study was identified for this variant, so BP7 was not applied.	cspec spliceai vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18

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