LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-05
Case ID: NM_007294.4_c.3541G_A_20261105_022354
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.3541G>A

BRCA1  · NP_009225.1:p.(Val1181Ile)  · NM_007294.4
GRCh37: chr17:41244007 C>T  ·  GRCh38: chr17:43091990 C>T
Gene: BRCA1 Transcript: NM_007294.4
Final call
Benign
BP5 very strong benign BP1 strong benign BP6 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA1
Transcript
NM_007294.4
Protein
NP_009225.1:p.(Val1181Ile)
gnomAD AF
4.5227562791965604e-05 (v4.1)
ClinVar
Benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Benign: the exact-variant clinical-history LR of 0.0005098224064769393 meets the ENIGMA BP5 Very Strong benign threshold.
2
Benign: residue 1181 is outside BRCA1 critical domains and SpliceAI maximum delta is only 0.003, meeting BP1 Strong.
3
Benign: the adjudicated criteria record a ClinVar expert-panel benign classification as BP6 Supporting.
Final determination: Under the ENIGMA BRCA1 VCEP Table 3, one Very Strong benign criterion plus one Supporting benign criterion satisfies the Benign classification rule.
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.3541G>A is a missense substitution, whereas the VCEP PVS1 rule applies to null variants.
cspec vcep_specifications_v1_2_2024_11_18 pvs1_variant_assessment
PS1 Not assessed Not assessed: SpliceAI max delta is 0.003, but no qualifying pathogenic or likely pathogenic comparator producing the same p.Val1181Ile substitution was established.
cspec PMID:16267036 PMID:21203900 spliceai
PS2 N/A Not applicable: ENIGMA says PS2 must not be used because BRCA1/2-related cancers are relatively common and de novo predictive capacity is uncalibrated.
vcep_specifications_v1_2_2024_11_18
PS3 Not assessed Not assessed: no PS3/BS3-calibrated functional assay entry was found for c.3541G>A in ENIGMA Table 9 or the supplementary functional datasets.
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 PMID:31131967
PS4 Not assessed Not assessed: variant-specific reports lack matched control counts or a case-control p-value, odds ratio, and confidence interval meeting the ENIGMA PS4 rule.
cspec vcep_specifications_v1_2_2024_11_18 PMID:21203900 PMID:16267036
PM1 N/A Not applicable: ENIGMA says not to use PM1, and residue 1181 lies outside the defined RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857 domains.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not met Not met: the variant is present in both required controls, at 19/236686 alleles in v2.1 non-cancer exomes and 2/147900 in v3.1 non-cancer genomes.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no Fanconi Anemia phenotype, qualifying second BRCA1 variant, phase, or Table 6 PM3 points are documented for c.3541G>A.
cspec PMID:16267036 PMID:21203900
PM4 N/A Not applicable: the variant is missense, not an in-frame length change or stop-loss variant covered by PM4.
cspec vcep_specifications_v1_2_2024_11_18 pvs1_variant_assessment
PM5 N/A Not applicable: ENIGMA does not use classic missense PM5, and c.3541G>A is a missense variant rather than a protein-termination-codon variant.
cspec vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable: ENIGMA says PM6 must not be used because BRCA1/2-related cancers are relatively common and de novo predictive capacity is uncalibrated.
vcep_specifications_v1_2_2024_11_18
PP1 Not assessed Not assessed: the exact variant row contains no segregation LR, so the VCEP's quantitative PP1 requirement cannot be evaluated or strength-assigned.
vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:31131967
PP2 N/A Not applicable: ENIGMA says not to use PP2 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 score 0.003 is below the VCEP PP3 splice-impact threshold of 0.2.
cspec vcep_specifications_v1_2_2024_11_18 spliceai
PP4 Not met Not met: Li et al. clinical-history LR 0.0005098224064769393 ≥ 2.08? No, so the ENIGMA PP4 supporting threshold is not reached.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5 N/A Not applicable: the ENIGMA specification explicitly states Do not use PP5, regardless of the ClinVar expert-panel assertion.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
BA1 Not met Not met: maximum specified non-cancer FAF is 0.00027671, below the ENIGMA BA1 threshold of >0.001.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS1 Not assessed Not assessed: v2.1 non-cancer maximum FAF 0.00027671 exceeds the BS1 Strong threshold, but required read depth ≥20 is unavailable.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: one gnomAD homozygote is frequency-based evidence, which ENIGMA excludes from BS2 point assignment without phenotyped cohort data.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: no BS3-calibrated protein or combined mRNA/protein assay result was found for c.3541G>A in the governing ENIGMA files.
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 PMID:31131967
BS4 Not assessed Not assessed: the exact variant row contains no segregation LR, so the VCEP's quantitative BS4 requirement cannot be evaluated or strength-assigned.
vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:31131967
BP1 Met Met at strong: residue 1181 is outside all defined BRCA1 critical domains and SpliceAI max delta 0.003 is below the ≤0.1 threshold.
cspec spliceai vcep_appendices_v1_2_2024_11_18
BP2 N/A Not applicable: the ENIGMA BRCA1 specification says BP2 is not used and is applied only in the context of BS2.
cspec
BP3 N/A Not applicable: BP3 is limited to in-frame deletions or insertions in repetitive regions without known function, not missense substitutions.
cspec vcep_specifications_v1_2_2024_11_18 pvs1_variant_assessment
BP4 N/A Not applicable: p.Val1181Ile is outside the VCEP-defined BRCA1 clinically important functional domains required for the BP4 missense path.
cspec vcep_specifications_v1_2_2024_11_18
BP5 Met Met, Very Strong: Li et al. clinical-history LR 0.0005098224064769393 ≤ 0.00285, satisfying the ENIGMA BP5 Very Strong threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6 Met Not applicable: the ENIGMA specification explicitly states Do not use BP6, so the ClinVar benign assertion cannot establish BP6.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
BP7 Not assessed Not assessed: BP7_Strong (RNA) could cover this out-of-domain missense variant, but no qualifying mRNA-only assay result is available.
cspec vcep_specifications_v1_2_2024_11_18
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