LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-08
Case ID: NM_007294.4_c.1222A_G_20261008_160513
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.1222A>G

BRCA1  · NP_009225.1:p.(Lys408Glu)  · NM_007294.4
GRCh37: chr17:41246326 T>C  ·  GRCh38: chr17:43094309 T>C
Gene: BRCA1 Transcript: NM_007294.4
Final call
Benign
BS3 strong 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.(Lys408Glu)
gnomAD AF
2.539935844937536e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Benign evidence: BS3 Strong is supported by a calibrated neutral protein-function result of 0.04 for this exact variant.
2
Benign evidence: BP1 Strong is supported because residue 408 is outside critical BRCA1 domains and SpliceAI is 0.035.
3
The two Strong benign criteria total -8 ENIGMA points, meeting the Benign threshold of <= -7.
Final determination: Under ENIGMA BRCA1 Version 1.2 Table 3, two Strong benign criteria are scored as -4 each, and a total of -8 is classified as Benign (threshold <= -7).
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.1222A>G is missense, p.(Lys408Glu), not an ENIGMA PVS1 null-variant class.
cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PS1 Not met Not met: SpliceAI max delta is 0.035, but no qualifying previously pathogenic same-amino-acid comparator was found.
cspec
PS2 N/A Not applicable: the ENIGMA specification explicitly says PS2 should not be used because de novo occurrences lack calibrated predictive value for BRCA1/2 cancers.
vcep_specifications_v1_2_2024_11_18
PS3 Not met Not met: ENIGMA Table 9 assigns BS3 Strong, with calibrated protein-function result 0.04 classified as likely neutral rather than damaging.
vcep_specifications_table9_v1_2_2024_11_18 cspec
PS4 Not assessed Not assessed: no exact-variant case-control OR, confidence interval, or p-value was available to evaluate the PS4 thresholds (p <=0.05 and OR >=4).
cspec
PM1 Not met Not met: Lys408 lies outside BRCA1 RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857, and VCEP PM1 is not used.
cspec vcep_specifications_v1_2_2024_11_18
PM2 Not met Not met: the variant is present at AF 4.23e-06 in gnomAD v2.1 non-cancer exomes, so ENIGMA PM2 absence from both datasets is not satisfied.
cspec gnomad_v2 vcep_supplementarytables_v1_2_2024_11_18
PM3 Not assessed Not assessed: the variant has no documented Fanconi-anemia phenotype, pathogenic partner, or qualifying trans-phase proband evidence needed for ENIGMA PM3 points.
cspec vcep_humu_40_1557_s001
PM4 N/A Not applicable: p.(Lys408Glu) is a missense substitution with no protein-length change, and ENIGMA explicitly does not use PM4.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: c.1222A>G is missense, whereas ENIGMA PM5 is reserved for exon-specific protein-termination-codon variants.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM6 N/A Not applicable: the governing ENIGMA BRCA1/2 framework marks PM6 as not applicable, regardless of any unconfirmed de novo observation.
vcep_specifications_v1_2_2024_11_18
PP1 Not assessed Not assessed: the exact-variant VCEP row has no segregation LR, so PP1's supporting threshold of LR ≥2.08:1 cannot be evaluated.
vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001
PP2 Not met Not met: ENIGMA explicitly disallows PP2 for BRCA1 because the gene has a high frequency of benign missense variation.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Not met Not met: missense REVEL 0.55 is below the ClinGen SVI supporting PP3 threshold of 0.644.
cspec revel
PP4 N/A Not applicable: combined clinical LR 1.8748372548618257 >= 2.08? no, placing it within ENIGMA's neutral PP4 interval.
vcep_pmid_31853058_brca1_clinical_history_lr vcep_humu_40_1557_s001 cspec
PP5 N/A Not applicable: ClinVar has zero expert-panel submissions for the exact variant, so ordinary laboratory labels cannot trigger PP5.
clinvar cspec
BA1 Not met Not met: gnomAD v2.1 non-cancer exome AF 4.23e-06 is below the ENIGMA BA1 threshold of 0.001.
cspec gnomad_v2
BS1 Not met Not met: gnomAD v2.1 non-cancer exome AF 4.23e-06 is below the ENIGMA BS1-supporting lower threshold of 0.00002.
cspec gnomad_v2
BS2 Not assessed Not assessed: gnomAD shows zero homozygotes, but no qualifying phenotyped healthy-adult observations or ENIGMA BS2 point total is available.
cspec gnomad_v2 vcep_appendices_v1_2_2024_11_18
BS3 Met Met, Strong: ENIGMA Table 9 pre-assigns BS3 Strong after a calibrated protein assay reported a likely neutral result of 0.04.
vcep_specifications_table9_v1_2_2024_11_18 cspec
BS4 Not assessed Not assessed: the exact-variant VCEP row has no segregation LR, while its combined LR 1.8748 is non-informative and cannot establish BS4.
vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1 Met Met, strong: residue 408 is outside all VCEP critical domains and SpliceAI max delta 0.035 is below the <=0.1 no-splicing threshold.
cspec vcep_specifications_v1_2_2024_11_18 PMID:31911673
BP2 N/A Not applicable: ENIGMA explicitly prohibits BP2 for BRCA1/2 and permits it only in the context of BS2.
cspec
BP3 N/A Not applicable: c.1222A>G is missense, not an in-frame insertion/deletion, and ENIGMA explicitly does not use BP3.
cspec vcep_specifications_v1_2_2024_11_18
BP4 Not met Not met: missense REVEL 0.55 exceeds the ClinGen SVI supporting BP4 threshold of <=0.29.
cspec revel
BP5 N/A Not applicable: combined clinical LR 1.8748372548618257 <= 0.48? no, placing it in ENIGMA's neutral BP5 interval.
vcep_pmid_31853058_brca1_clinical_history_lr vcep_humu_40_1557_s001 cspec
BP6 N/A Not applicable: ClinVar has zero expert-panel submissions for the exact variant, so ordinary laboratory benign labels cannot trigger BP6.
clinvar cspec
BP7 N/A Not applicable: c.1222A>G is missense, producing p.Lys408Glu rather than a synonymous change.
cspec
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