LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-16
Case ID: NM_007294.4_c.3245C_T_20261016_170427
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.3245C>T

BRCA1  · NP_009225.1:p.(Ala1082Val)  · NM_007294.4
GRCh37: chr17:41244303 G>A  ·  GRCh38: chr17:43092286 G>A
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.(Ala1082Val)
gnomAD AF
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS: BP1_Strong is met because Ala1082 lies outside the specified BRCA1 domains and SpliceAI is 0.008.
2
VUS: No additional benign or pathogenic criterion combination is met under ENIGMA Table 3.
Final determination: Under ENIGMA Table 3, one strong benign criterion alone is insufficient for Likely Benign, so with no qualifying pathogenic combination the classification remains 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.3245C>T causes p.Ala1082Val, a missense substitution outside the ENIGMA null-variant PVS1 scope.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PS1 Not assessed Not assessed: SpliceAI is 0.008, but no qualifying pathogenic or likely pathogenic alternate nucleotide change producing p.Ala1082Val was identified.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
PS2 N/A Not applicable: the ENIGMA specification explicitly says PS2 should not be used because de novo predictive capacity is uncalibrated for relatively common BRCA1/2-related cancers.
cspec
PS3 Not assessed Not assessed: no variant-specific calibrated protein or combined mRNA/protein assay result or pre-assigned PS3 code was found for c.3245C>T.
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 PMID:25230021 PMID:31911673
PS4 Not assessed Not assessed: no variant-specific case-control p-value, OR, or confidence interval is available to evaluate p-value ≤0.05 and OR ≥4 with a lower CI excluding 2.0.
cspec clinvar
PM1 N/A Not applicable: ENIGMA explicitly says PM1 is not used, and Ala1082 lies outside the listed BRCA1 critical functional domains.
vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 cspec
PM2 Not assessed Not assessed: the variant is absent from both specified non-cancer gnomAD datasets, but required average read depth (>=25) is not reported.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM3 Not assessed Not assessed: no documented co-occurring BRCA1 pathogenic variant, phase information, or qualifying Fanconi Anemia phenotype is available.
vcep_specifications_v1_2_2024_11_18
PM4 N/A Not applicable: p.Ala1082Val is a missense substitution with no protein length change, while ENIGMA explicitly says PM4 is not used.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: classic missense PM5 is excluded by ENIGMA, and PM5_PTC is limited to PVS1-annotated protein-termination variants.
vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM6 N/A Not applicable: the ENIGMA specification explicitly says PM6 should not be used because de novo predictive capacity is uncalibrated for relatively common BRCA1/2-related cancers.
cspec
PP1 Not assessed Not assessed: no quantitative co-segregation likelihood ratio or documented informative affected-family meioses is available for this variant.
cspec
PP2 N/A Not applicable: ENIGMA excludes PP2 because missense variants are not a common BRCA1 pathogenic mechanism and benign missense variation is frequent.
vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP3 Not met Not met: SpliceAI maximum delta 0.008 is below the VCEP PP3 splice threshold of ≥0.2, and the variant is outside the domain required for the protein-impact path.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 spliceai bayesdel
PP4 Not assessed Not assessed: no combined multifactorial clinical LR is available for comparison with the PP4 supporting threshold of LR ≥2.08:1.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 vcep_pmid_17924331_easton_2007_ajhg PMID:17924331
PP5 N/A Not applicable: ENIGMA explicitly says PP5 is not for use, so no reputable-source pathogenic report can activate this criterion.
cspec vcep_specifications_v1_2_2024_11_18
BA1 Not assessed Not assessed: gnomAD non-cancer records are absent, but the required BA1 FAF threshold (>0.001) and read-depth quality gate are not reported.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS1 Not assessed Not assessed: gnomAD non-cancer records are absent, but the required BS1 FAF thresholds (>0.00002) and read-depth quality gate are not reported.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS2 Not assessed Not assessed: no qualifying healthy-adult, zygosity, Fanconi Anemia, follow-up, or BS2 point data are available.
cspec vcep_appendices_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
BS3 Not assessed Not assessed: no variant-specific calibrated benign protein or combined mRNA/protein assay result or pre-assigned BS3 code was found for c.3245C>T.
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 PMID:25230021 PMID:31911673
BS4 Not assessed Not assessed: no quantitative non-segregation likelihood ratio or documented affected-family discordance is available for this variant.
cspec
BP1 Met Met at Strong: Ala1082 is outside ENIGMA domains and SpliceAI maximum delta is 0.008, below the ≤0.1 no-splicing threshold.
vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 cspec spliceai
BP2 N/A Not applicable: the ENIGMA specification states BP2 is not used and is applied only in the context of BS2.
vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: p.Ala1082Val is not an in-frame deletion or insertion, and ENIGMA explicitly says BP3 is not used.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: BP4's missense path requires a variant inside a VCEP-defined functional domain, whereas p.Ala1082Val lies outside all listed BRCA1 domains.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai bayesdel
BP5 Not assessed Not assessed: no combined clinical LR is available for the governing BP5 comparison LR ≤0.48, so the benign-supporting threshold cannot be tested.
cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 vcep_pmid_17924331_easton_2007_ajhg PMID:17924331
BP6 N/A Not applicable: ENIGMA explicitly says BP6 is not for use, so reputable-source benign reports cannot activate this criterion.
cspec vcep_specifications_v1_2_2024_11_18
BP7 Not assessed Not assessed: The variant is eligible for BP7_Strong (RNA), but no qualifying mRNA-only assay result is available; SpliceAI 0.008 alone is insufficient.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 spliceai
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