LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-16
Case ID: NM_007294.4_c.4481A_G_20261016_022029
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.4481A>G

BRCA1  · NP_009225.1:p.(Glu1494Gly)  · NM_007294.4
GRCh37: chr17:41228508 T>C  ·  GRCh38: chr17:43076491 T>C
Gene: BRCA1 Transcript: NM_007294.4
Final call
VUS
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA1
Transcript
NM_007294.4
Protein
NP_009225.1:p.(Glu1494Gly)
gnomAD AF
3.0984463150797666e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
All three requested consequence/LOF criteria are not applicable: the variant is a BRCA1 missense substitution, and ENIGMA v1.2 excludes PVS1, PM4, and BP3 for this consequence class.
2
The governing ENIGMA BRCA1/2 V1.2 framework controls all five requested criteria.
3
No requested criterion is met: PS1 lacks a pathogenic same-amino-acid comparator, while PM1, PM5, PP2, and BP1 are not applicable under explicit VCEP rules.
4
The only same-residue alternate found in the governing functional tables, p.Glu1494Lys, is classified as no functional impact/Not Pathogenic.
5
PS2 and PM6 are not applicable under the governing ENIGMA BRCA1/2 VCEP specification.
6
PP1 and BS4 remain not assessed because no variant-specific segregation or non-segregation evidence was available; the clinical-history LR row was not used as a segregation result.
7
Neither PS3 nor BS3 is assessed because the governing ENIGMA variant-specific functional-assay resources contain no entry for NM_007294.4:c.4481A>G (p.Glu1494Gly/p.E1494G), and no separate variant-specific protein-function assay evidence was available in the case bundle.
8
For this missense variant, the governing ENIGMA specification was used first. PS4 lacks required case-control statistics; PP4 and BP5 use the exact Li clinical-history LR of 1.098592032317503, which is below pathogenic-supporting and above benign-supporting thresholds; PP5 and BP6 are excluded by ENIGMA and lack eligible ClinVar expert-panel classifications.
9
The variant is missense, so PP3 and BP4 were assessed through the REVEL protein-impact path only; BP7 is not applicable.
10
REVEL 0.492 is below the supporting PP3 threshold of 0.644 and above the supporting BP4 threshold of 0.29, so neither computational code is met.
Final determination: Under ENIGMA BRCA1/2 VCEP Version 1.2 Table 3, the absence of any met pathogenic or benign evidence combination results in VUS.
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 Not applicable: c.4481A>G is a missense substitution, whereas ENIGMA PVS1 is restricted to defined loss-of-function variant classes.
cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PS1 Not met Not met: the only same-residue comparator, p.Glu1494Lys, is ENIGMA-classified Not Pathogenic rather than pathogenic or likely pathogenic.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
PS2 N/A Not applicable: ENIGMA v1.2 prohibits PS2 for BRCA1/2 because de novo cancer-occurrence predictive capacity is uncalibrated.
cspec
PS3 Not assessed Not assessed: ENIGMA Table 9 and ST4 contain no c.4481A>G/p.Glu1494Gly/p.E1494G entry assigning damaging functional evidence.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4 Not assessed Not assessed: no variant-specific case-control odds ratio, p-value, or confidence interval is available for the PS4 requirements.
cspec
PM1 N/A Not applicable: ENIGMA prohibits standalone PM1, and residue E1494 lies outside the approved BRCA1 RING, coiled-coil, and BRCT domains.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not assessed Not assessed: both required non-cancer datasets failed, and all-comers data show 1 and 5 alleles rather than absence.
cspec gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no documented Fanconi Anemia phenotype or phased co-occurring pathogenic/likely pathogenic BRCA1 variant is available for the 2-point PM3 threshold.
vcep_specifications_v1_2_2024_11_18 gnomad_v2 gnomad_v4
PM4 N/A Not applicable: p.(Glu1494Gly) changes one amino acid without changing protein length, and ENIGMA marks PM4 as do not use.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: PM5 is restricted by ENIGMA to genomic PTC variants, whereas c.4481A>G produces the missense substitution p.Glu1494Gly.
cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM6 N/A Not applicable: ENIGMA v1.2 prohibits PM6 for BRCA1/2 because de novo cancer-occurrence predictive capacity is uncalibrated.
cspec
PP1 Not assessed Not assessed: no variant-specific segregation LR or affected-family-member genotype data was available to compare with the PP1 threshold of LR >=2.08.
cspec vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18
PP2 N/A Not applicable: the governing ENIGMA specification explicitly prohibits PP2 for BRCA1/2 interpretation.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Not met Not met: REVEL 0.492 is below the 0.644 supporting PP3 threshold for missense variants.
cspec revel
PP4 Not met Not met: clinical-history LR 1.098592032317503 >= 2.08? no, so it does not reach the ENIGMA PP4 Supporting threshold.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 PMID:17924331
PP5 N/A Not applicable: ENIGMA says do not use PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification.
cspec clinvar
BA1 Not assessed Not assessed: required non-cancer gnomAD frequencies failed, while available all-comers AFs (3.98e-06 and 3.10e-06) cannot establish BA1.
cspec gnomad_v2 gnomad_v4
BS1 Not assessed Not assessed: required non-cancer frequencies failed, and available all-comers AFs (3.98e-06 and 3.10e-06) are not governing BS1 evidence.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: no qualifying phenotyped adult or phase evidence is provided, and VCEP excludes gnomAD frequency-only homozygotes from BS2.
cspec gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: ENIGMA Table 9 and ST4 contain no c.4481A>G/p.Glu1494Gly/p.E1494G entry assigning benign functional evidence.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4 Not assessed Not assessed: no variant-specific non-segregation LR or affected-family-member genotype data was available to compare with the BS4 threshold of LR <=0.48.
cspec vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18
BP1 N/A Not applicable: ENIGMA explicitly excludes missense prediction from BP1, despite E1494 lying outside its listed functional domains.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: ENIGMA BRCA1 VCEP specifies BP2 should not be used and limits it to the BS2 context.
vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: BP3 is explicitly unavailable in ENIGMA v1.2 and applies to benign in-frame indels in repetitive regions, not missense substitutions.
cspec vcep_specifications_v1_2_2024_11_18
BP4 Not met Not met: REVEL 0.492 exceeds the 0.29 supporting BP4 threshold for missense variants and is gray-zone.
cspec revel
BP5 Not met Not met: clinical-history LR 1.098592032317503 <= 0.48? no, so it does not reach the ENIGMA BP5 Supporting threshold.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 PMID:17924331
BP6 N/A Not applicable: ENIGMA says do not use BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification.
cspec clinvar
BP7 N/A Not applicable: c.4481A>G is missense, whereas BP7 applies only to synonymous or qualifying intronic variants.
cspec
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