LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-16
Case ID: NM_007294.4_c.3001G_A_20261016_191748
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.3001G>A

BRCA1  · NP_009225.1:p.(Glu1001Lys)  · NM_007294.4
GRCh37: chr17:41244547 C>T  ·  GRCh38: chr17:43092530 C>T
Gene: BRCA1 Transcript: NM_007294.4
Final call
VUS
BP1 strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA1
Transcript
NM_007294.4
Protein
NP_009225.1:p.(Glu1001Lys)
gnomAD AF
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS: BP1 (strong) is met because residue 1001 is outside approved BRCA1 domains and SpliceAI max delta is 0.004.
2
VUS: no pathogenic criterion is met, and BP1 (strong) lacks the additional benign evidence required for a benign call.
Final determination: Under ENIGMA Table 3, a single Strong benign criterion does not establish Likely Benign unless the required additional evidence condition is satisfied, so BP1_Strong alone leaves the variant as 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.3001G>A is a missense substitution, whereas ENIGMA PVS1 is limited to specified null variants such as nonsense, frameshift, splice-site, and exon-deletion variants.
pvs1_variant_assessment vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 cspec
PS1 Not met Not met: no VCEP-recorded pathogenic or likely pathogenic variant was identified with the same p.Glu1001Lys amino-acid substitution.
cspec vcep_specifications_v1_2_2024_11_18 spliceai
PS2 N/A Not applicable: the ENIGMA specification explicitly says not to use PS2 because de novo occurrences lack calibrated predictive value.
vcep_specifications_v1_2_2024_11_18
PS3 Not assessed Not assessed: no exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in the governing functional tables.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PS4 Not assessed Not assessed: no variant-specific case-control odds ratio, p-value, or confidence interval is available for the required PS4 comparison.
cspec
PM1 N/A Not applicable: ENIGMA explicitly says PM1 is not used, regardless of this residue's location outside its listed critical domains.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not assessed Not assessed: the variant is absent from required gnomAD non-cancer datasets, but regional average read depth of at least 25 is not documented.
cspec gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no documented same-gene pathogenic/likely pathogenic co-occurring variant, phase, or Fanconi Anemia phenotype is available to assign the VCEP's PM3 points.
cspec vcep_specifications_v1_2_2024_11_18
PM4 N/A Not applicable: p.(Glu1001Lys) is a missense substitution with no protein-length change, and ENIGMA explicitly says PM4 is not to be used.
pvs1_variant_assessment vcep_specifications_v1_2_2024_11_18 cspec
PM5 N/A Not applicable: ENIGMA excludes classic missense PM5 and reserves PM5 for genomic PTC variants annotated with PVS1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM6 N/A Not applicable: the ENIGMA specification explicitly says not to use PM6 because de novo occurrences lack calibrated predictive value.
vcep_specifications_v1_2_2024_11_18
PP1 Not assessed Not assessed: no quantitative cosegregation LR or affected-family genotype data are available to compare with the VCEP PP1 threshold of LR ≥2.08:1.
vcep_specifications_v1_2_2024_11_18
PP2 N/A Not applicable: ENIGMA says PP2 is not used because BRCA1 has a high frequency of benign missense variants.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Not met Not met: SpliceAI maximum delta 0.004 is below the VCEP PP3 splice threshold of ≥0.2 for this missense variant.
cspec spliceai vcep_specifications_v1_2_2024_11_18
PP4 Not assessed Not assessed: no combined clinical likelihood ratio is available, and the Li et al. table has no matching c.3001G>A row.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 vcep_pmid_17924331_easton_2007_ajhg PMID:17924331
PP5 N/A Not applicable: the ENIGMA BRCA1 VCEP explicitly prohibits use of PP5 regardless of reported pathogenic classifications.
cspec
BA1 Not met Not met: the qualifying gnomAD non-cancer datasets report no variant, so no filter allele frequency exceeds the ENIGMA BA1 threshold of 0.001.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: the qualifying gnomAD non-cancer datasets report no variant, so no filter allele frequency exceeds the ENIGMA BS1 threshold of 0.00002.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: no healthy-adult genotype observations or ENIGMA BS2 point count is available to reach the required threshold of 1, 2, or 4 points.
cspec
BS3 Not assessed Not assessed: no exact c.3001G>A, p.Glu1001Lys, or p.E1001K entry was found in the governing functional tables.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS4 Not assessed Not assessed: no quantitative negative-cosegregation LR or affected-family genotype data are available to compare with the VCEP BS4 threshold of LR ≤0.48:1.
vcep_specifications_v1_2_2024_11_18
BP1 Met Met at Strong: residue 1001 is outside approved domains and SpliceAI max delta 0.004 meets the ≤0.1 no-splicing requirement.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: the VCEP explicitly says BP2 is not used and is applied only in the context of BS2.
cspec vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: p.(E1001K) is missense rather than an in-frame indel in a nonfunctional repetitive region, and ENIGMA explicitly says BP3 is not to be used.
pvs1_variant_assessment vcep_specifications_v1_2_2024_11_18 cspec
BP4 N/A Not applicable: p.Glu1001Lys is a missense variant outside the VCEP-defined BRCA1 domains covered by the BP4 missense path.
cspec vcep_specifications_v1_2_2024_11_18
BP5 Not assessed Not assessed: no combined clinical likelihood ratio is available, and the Li et al. table has no matching c.3001G>A row.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 vcep_pmid_17924331_easton_2007_ajhg PMID:17924331
BP6 N/A Not applicable: the ENIGMA BRCA1 VCEP explicitly prohibits use of BP6 regardless of reported benign classifications.
cspec
BP7 N/A Not applicable: BP7 is restricted to silent or qualifying intronic variants, whereas p.Glu1001Lys is missense.
cspec vcep_specifications_v1_2_2024_11_18
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