LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-28
Case ID: NM_007294.4_c.2342A_C_20260928_184109
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.2342A>C

BRCA1  · NP_009225.1:p.(Glu781Ala)  · NM_007294.4
GRCh37: chr17:41245206 T>G  ·  GRCh38: chr17:43093189 T>G
Gene: BRCA1 Transcript: NM_007294.4
Final call
Likely Benign
BP1 strong PP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA1
Transcript
NM_007294.4
Protein
NP_009225.1:p.(Glu781Ala)
gnomAD AF
8.054722545788e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BP1 strong because p.Glu781Ala is outside the clinically important domains and SpliceAI 0.018 indicates no predicted splicing impact.
2
Likely Benign: PP4 supporting because the exact-variant clinical-history likelihood ratio is 3.1586, above the 2.08 threshold.
Final determination: Under the ENIGMA BRCA1 VCEP Version 1.2 conflicting-evidence point system, BP1 strong is -4 points and PP4 supporting is +1 point; the total of -3 falls within the Likely Benign range of -6 to -2.
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.2342A>C is a missense substitution with SpliceAI maximum delta 0.018, not a null or canonical splice-site variant.
cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
PS1 Not met Not met: no governing-VCEP pathogenic comparator for p.Glu781Ala/p.E781A was found, despite SpliceAI maximum delta 0.018 being below 0.1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
PS2 N/A Not applicable: ENIGMA explicitly prohibits PS2 because de novo occurrences are not calibrated for BRCA1/2-related cancers.
cspec
PS3 Not assessed Not assessed: no exact variant-specific functional assay entry or calibrated damaging result was found for c.2342A>C/p.Glu781Ala.
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 p-value, odds ratio, or confidence interval is available to apply the ENIGMA PS4 requirements.
cspec
PM1 N/A Not applicable: p.Glu781 lies outside ENIGMA domains aa 2-101, 1391-1424, and 1650-1857, while exon 11 has pathogenicity odds ratio <0.01.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:31911673
PM2 Not assessed Not assessed: the variant is absent from governing gnomAD non-cancer datasets, but the required regional average read depth of at least 25 is undocumented.
cspec gnomad_v2 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
PM3 Not assessed Not assessed: no Fanconi Anemia phenotype, co-occurrent pathogenic BRCA1 variant, or phase evidence is documented for this variant, so the VCEP PM3 point thresholds cannot be reached.
cspec
PM4 N/A Not applicable: p.Glu781Ala changes one amino acid without altering protein length, whereas ENIGMA PM4 covers in-frame length changes or stop-loss variants.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: c.2342A>C is missense p.Glu781Ala, whereas ENIGMA PM5 is reserved for 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: ENIGMA explicitly prohibits PM6 because de novo occurrences lack calibration in BRCA1/2-related cancers.
cspec
PP1 Not assessed Not assessed: no quantitative family co-segregation LR is available, and the separate clinical-history LR 3.158578379510139 is not segregation evidence.
cspec vcep_humu_40_1557_s001 vcep_pmid_31853058_brca1_clinical_history_lr
PP2 N/A Not applicable: ENIGMA explicitly excludes PP2 because missense variants are not a common BRCA1 pathogenic mechanism.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Not met Not met: missense REVEL score 0.423 is below the >=0.644 supporting PP3 threshold.
cspec revel vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP4 Met Met at Supporting: the exact-variant clinical-history likelihood ratio is 3.1586, satisfying the ENIGMA PP4 threshold 3.1586 >= 2.08.
cspec PMID:31853058
PP5 N/A Not applicable: ClinVar has no exact-variant Expert Panel Pathogenic or Likely pathogenic classification eligible for PP5.
cspec clinvar
BA1 Not met Not met: the variant is absent from governing gnomAD v2.1/v3.1 non-cancer datasets, so no filter allele frequency exceeds the ENIGMA BA1 threshold of 0.001.
cspec gnomad_v2 gnomad_v4 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS1 Not met Not met: the variant is absent from governing gnomAD v2.1/v3.1 non-cancer datasets, and the available gnomAD v4.1 grpmax FAF is 5.42e-06 below 0.00002.
cspec gnomad_v2 gnomad_v4 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS2 Not assessed Not assessed: gnomAD reports zero homozygotes, but ENIGMA BS2 requires phenotyped clinical-cohort observations with phase and age or follow-up information.
cspec gnomad_v4 vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS3 Not assessed Not assessed: no exact variant-specific functional assay entry or calibrated benign result was found for c.2342A>C/p.Glu781Ala.
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 affected-family non-segregation LR is available, while the reported clinical-history LR 3.158578379510139 is not BS4 evidence.
cspec vcep_humu_40_1557_s001 vcep_pmid_31853058_brca1_clinical_history_lr
BP1 Met Met, strong: p.Glu781Ala is outside all ENIGMA domains and SpliceAI maximum delta 0.018 is below the <=0.1 threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: the BRCA1 VCEP explicitly says not to use BP2 and limits it to BS2, with no BP2 strength assigned.
cspec
BP3 N/A Not applicable: p.Glu781Ala is a missense change, not an in-frame insertion or deletion in a repetitive region without known function.
cspec vcep_specifications_v1_2_2024_11_18
BP4 Not met Not met: missense REVEL score 0.423 exceeds the <=0.29 supporting BP4 threshold and is therefore gray-zone.
cspec revel vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP5 Not met Not met: the exact-variant clinical-history LR is 3.1586, failing the ENIGMA BP5 comparison 3.1586 <= 0.48.
cspec PMID:31853058
BP6 N/A Not applicable: ClinVar has no exact-variant Expert Panel Benign or Likely benign classification eligible for BP6.
cspec clinvar
BP7 N/A Not applicable: c.2342A>C is missense, whereas BP7 is restricted to synonymous variants.
cspec
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