LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-30
Case ID: NM_007294.3_c.5522G_A_20260430_173543
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.3:c.5522G>A

BRCA1  · NP_009225.1:p.(Ser1841Asn)  · NM_007294.3
GRCh37: chr17:41197765 C>T  ·  GRCh38: chr17:43045748 C>T
Gene: BRCA1 Transcript: NM_007294.3
Final call
BP4_Supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA1
Transcript
NM_007294.3
Protein
NP_009225.1:p.(Ser1841Asn)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The BRCA1 c.5522G>A (p.Ser1841Asn; p.S1841N) variant has been reported in ClinVar with conflicting interpretations, including an expert-panel classification of uncertain significance.
2
This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1,614,094 alleles; AF 6.20e-07; highest South Asian AF 1.10e-05), so it is very rare but not absent from population databases.
3
In ENIGMA-calibrated functional studies, results were discordant, ranging from loss-of-function to intermediate effects, and ENIGMA Table 9 does not assign PS3 or BS3 for this variant.
4
This missense change lies in the BRCA1 BRCT repeats, and the BRCA1 ENIGMA computational rule supports BP4 because BayesDel no-AF is 0.144191 (threshold <=0.15) and SpliceAI maximum delta is 0.00 (threshold <=0.1); REVEL is 0.626 but is not the deciding rule in this VCEP framework.
Final determination: Uncertain Significance because only one supporting benign criterion is met (BP4), which does not satisfy the ENIGMA Table 3 threshold for Likely Benign or Benign, and no pathogenic combination rule is met.
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 variant is a missense substitution, p.(Ser1841Asn) / p.(S1841N), and does not fall into the BRCA1 loss-of-function variant categories used for PVS1. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, so available evidence does not support a PVS1-based loss-of-function mechanism for this variant.
pvs1_variant_assessment pvs1_gene_context spliceai vcep_specifications_v1_2_2024_11_18
PS1 Not assessed No evidence was identified showing that this variant produces the same established pathogenic protein or splicing consequence as another previously classified BRCA1 variant, so PS1 was not assessed.
vcep_specifications_v1_2_2024_11_18 spliceai
PS2 N/A De novo evidence is not used for BRCA1 in this VCEP framework, so PS2 is not applicable.
vcep_specifications_v1_2_2024_11_18
PS3 Not met ENIGMA-calibrated functional evidence for this variant is discordant across multiple studies, with reported results ranging from loss-of-function to intermediate effects. Because the available calibrated studies do not show a consistent damaging effect, PS3 is not met.
vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4 Not assessed No case-control analysis or formal evidence showing that this variant is significantly enriched in affected individuals compared with controls was identified, so PS4 was not assessed.
clinvar vcep_specifications_v1_2_2024_11_18
PM1 N/A PM1 is not applicable in the BRCA1 ENIGMA specification.
vcep_specifications_v1_2_2024_11_18
PM2 Not met This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 1/1,614,094 alleles (AF 6.20e-07; highest population AF 1.10e-05 in South Asian individuals). Because the variant is not absent from population databases, PM2 is not met.
gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
PM3 Not assessed No evidence was identified that this variant was observed with an appropriate BRCA1-related Fanconi anemia phenotype and a qualifying second BRCA1 variant in trans, so PM3 was not assessed.
vcep_specifications_v1_2_2024_11_18
PM4 N/A PM4 is not applicable in the BRCA1 ENIGMA specification.
vcep_specifications_v1_2_2024_11_18
PM5 N/A Under the BRCA1 ENIGMA specification, PM5 is used here for protein-truncating variants in eligible exons. This variant is a missense substitution, so PM5 is not applicable.
vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A PM6 is not applicable in the BRCA1 ENIGMA specification.
vcep_specifications_v1_2_2024_11_18
PP1 Not assessed No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.
vcep_specifications_v1_2_2024_11_18
PP2 N/A PP2 is not applicable in the BRCA1 ENIGMA specification.
vcep_specifications_v1_2_2024_11_18
PP3 Not met This missense variant is located in the BRCA1 BRCT repeats, but the BRCA1 ENIGMA PP3 rule is not met because BayesDel no-AF is 0.144191, which is below the pathogenic threshold of 0.28, and SpliceAI predicts no splice effect with a maximum delta score of 0.00, below the splicing threshold of 0.2. REVEL is 0.626, but the gene-specific VCEP computational rule is based on BayesDel and SpliceAI rather than REVEL.
vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 bayesdel spliceai revel
PP4 Not assessed No variant-specific multifactorial clinical-history likelihood ratio meeting the BRCA1 ENIGMA PP4 thresholds was identified for this variant, so PP4 was not assessed.
vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 vcep_specifications_v1_2_2024_11_18
PP5 N/A PP5 is not applicable in the BRCA1 ENIGMA specification.
vcep_specifications_v1_2_2024_11_18
BA1 Not met This variant does not meet the BRCA1 ENIGMA BA1 threshold. It is absent from gnomAD v2.1 and present in gnomAD v4.1 at AF 6.20e-07, which is far below the BA1 stand-alone threshold of 0.001.
gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
BS1 Not met This variant does not meet the BRCA1 ENIGMA BS1 threshold. The observed gnomAD v4.1 allele frequency is 6.20e-07, which is below both the supporting threshold of 0.00002 and the strong threshold of 0.0001.
gnomad_v4 vcep_specifications_v1_2_2024_11_18
BS2 Not assessed No qualifying data were identified showing this variant in individuals without features of BRCA1-related Fanconi anemia under the BRCA1 ENIGMA point-based BS2 framework, so BS2 was not assessed.
vcep_specifications_v1_2_2024_11_18
BS3 Not met ENIGMA-calibrated functional studies for this variant are discordant and do not consistently show a normal or non-damaging effect. Because ENIGMA Table 9 does not assign BS3 for this variant, BS3 is not met.
vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4 Not assessed No quantitative non-segregation data were identified for this variant, so BS4 was not assessed.
vcep_specifications_v1_2_2024_11_18
BP1 Not met This missense variant is located in the BRCA1 BRCT repeats, a clinically important functional domain spanning amino acids 1650-1857, so it does not meet the BRCA1 ENIGMA BP1 rule for missense variants outside important domains. SpliceAI also predicts no splice effect, but the domain requirement is not met.
vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BP2 N/A BP2 is not applicable in the BRCA1 ENIGMA specification.
vcep_specifications_v1_2_2024_11_18
BP3 N/A BP3 is not applicable in the BRCA1 ENIGMA specification.
vcep_specifications_v1_2_2024_11_18
BP4 Met This missense variant is located in the BRCA1 BRCT repeats, and the BRCA1 ENIGMA BP4 rule is met because BayesDel no-AF is 0.144191, which is at or below the benign threshold of 0.15, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, which is at or below the threshold of 0.1. REVEL is 0.626, but the gene-specific BRCA1 VCEP computational rule is based on BayesDel and SpliceAI rather than REVEL.
vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 bayesdel spliceai revel
BP5 Not assessed No variant-specific multifactorial clinical-history likelihood ratio meeting the BRCA1 ENIGMA BP5 thresholds was identified for this variant, so BP5 was not assessed.
vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 vcep_specifications_v1_2_2024_11_18
BP6 N/A BP6 is not applicable in the BRCA1 ENIGMA specification.
vcep_specifications_v1_2_2024_11_18
BP7 N/A This variant is a missense substitution within a clinically important BRCT domain, and no qualifying RNA-only evidence showing a benign transcript effect was identified. The BRCA1 ENIGMA BP7 rules do not apply to this variant in its current evidence context.
vcep_specifications_v1_2_2024_11_18 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.