LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-09
Case ID: NM_007294.4_c.1106_1108del_20261109_193830
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.1106_1108del

BRCA1  · NP_009225.1:p.(Asp369del)  · NM_007294.4
GRCh37: chr17:41246439 ACAT>A  ·  GRCh38: chr17:43094422 ACAT>A
Gene: BRCA1 Transcript: NM_007294.4
Final call
Benign
BS1 supporting BS3 strong BS4 strong BP1 strong 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.(Asp369del)
gnomAD AF
9.665175999137569e-05 (v4.1)
ClinVar
Benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BS3 Strong: calibrated protein function resembled benign controls with assay score 0.07.
2
BS4 Strong: segregation LR 0.0116 was below the benign threshold of 0.05:1.
3
BP1 Strong: the deletion is outside defined BRCA1 functional domains and has low predicted splice impact.
4
BS1 Supporting: maximum non-cancer FAF was 0.00005945, within the ENIGMA BS1 range.
5
BP6 Supporting benign: an expert panel source classified the variant as benign.
Final determination: The ENIGMA BRCA1 Table 3 benign rule is satisfied because at least two Strong benign criteria, BS3 Strong and BS4 Strong, are present.
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.1106_1108del is a three-nucleotide in-frame p.Asp369del, not one of the VCEP-defined null variant types eligible for PVS1.
pvs1_variant_assessment cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PS1 N/A Not applicable: p.(Asp369del) is an in-frame deletion, whereas ENIGMA PS1 requires a predicted missense substitution or precisely matching pathogenic splicing event.
cspec vcep_specifications_v1_2_2024_11_18
PS2 N/A Not applicable: the ENIGMA BRCA1 VCEP explicitly says PS2 is not used for de novo occurrences in BRCA1/2-related cancers.
cspec
PS3 Not met Not met: ENIGMA Table 9 assigns BS3 Strong because the calibrated protein-function assay score was 0.07 and resembled benign controls.
vcep_specifications_table9_v1_2_2024_11_18 cspec
PS4 Not assessed Not assessed: exact-variant reports lack an ethnicity-matched control comparison and the counts needed to test p-value <=0.05, OR >=4, and lower CI >2.0.
cspec vcep_specifications_v1_2_2024_11_18 PMID:11044354 PMID:16267036 PMID:17924331
PM1 N/A Not applicable: ENIGMA says PM1 is not used, and residue 369 lies outside BRCA1 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 PMID:11044354
PM2 N/A Not applicable: ENIGMA excludes PM2 for deletion variants, and this variant is an in-frame deletion present in both specified datasets.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: D369del was reported in trans with BRCA1 5385insC, but the required Fanconi Anemia phenotype and Table 6 point-assigning observations are unavailable.
cspec vcep_specifications_v1_2_2024_11_18 PMID:16267036
PM4 N/A Not applicable: although p.Asp369del changes protein length, the BRCA1 VCEP explicitly says PM4 is not used for this framework.
pvs1_variant_assessment cspec vcep_specifications_v1_2_2024_11_18 PMID:11044354
PM5 N/A Not applicable: ENIGMA does not use ordinary missense PM5, and PM5_PTC is restricted to protein-termination-codon variants annotated PVS1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable: the ENIGMA BRCA1 VCEP explicitly says PM6 is not used for uncalibrated de novo occurrences.
cspec
PP1 Not met Not met: the segregation LR is 0.0116, below the ENIGMA PP1 Supporting threshold of 2.08:1.
vcep_humu_40_1557_s001 PMID:31131967 cspec
PP2 N/A Not applicable: ENIGMA says PP2 is not used for BRCA1, which has a high frequency of benign missense variants, and this variant is an in-frame deletion.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Not met Not met: SpliceAI maximum delta 0.068 is below the VCEP PP3 splice-impact threshold of 0.2, and residue 369 lies outside the protein-impact domains.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 spliceai
PP4 Not assessed Not assessed: no eligible exact-variant combined clinical LR was found to test the ENIGMA PP4 thresholds of >=2.08, >=4.3, >=18.7, or >=350.
cspec vcep_specifications_v1_2_2024_11_18 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 specification explicitly states that PP5 is not to be used.
cspec vcep_specifications_v1_2_2024_11_18
BA1 Not met Not met: maximum non-cancer FAF was 0.00005945, 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 Met Met at Supporting: gnomAD v2.1 non-cancer maximum FAF 0.00005945 falls between >0.00002 and <=0.0001.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: gnomAD reports zero homozygotes, while no qualifying phenotyped healthy-adult observation or BS2 point assignment is available.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS3 Met Met, Strong: ENIGMA Table 9 reports protein function similar to benign controls in one calibrated study, with assay score 0.07.
vcep_specifications_table9_v1_2_2024_11_18 cspec
BS4 Met Met, Strong: the segregation LR is 0.0116, below the ENIGMA BS4 Strong threshold of 0.05:1.
vcep_humu_40_1557_s001 PMID:31131967 cspec
BP1 Met Met at Strong: p.Asp369del is outside approved BRCA1 domains and SpliceAI maximum delta 0.068 is below the ENIGMA no-splicing threshold of 0.1.
cspec vcep_specifications_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: the VCEP explicitly says BP2 is not used and permits it only in the context of BS2.
cspec vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: despite being an in-frame deletion, BP3 is explicitly excluded by the BRCA1 VCEP and captured through bioinformatic/domain analysis instead.
pvs1_variant_assessment cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: p.Asp369del is outside the VCEP-defined functional domains required for BP4 on an in-frame deletion, despite SpliceAI maximum delta 0.068.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 spliceai
BP5 Not assessed Not assessed: no eligible exact-variant LR was found to test BP5's required downward inequalities, including LR <=0.48, <=0.23, <=0.05, or <=0.00285.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 vcep_pmid_17924331_easton_2007_ajhg PMID:17924331
BP6 Met Not applicable: the ENIGMA BRCA1 specification explicitly states that BP6 is not to be used.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
BP7 N/A Not applicable: BP7 covers silent or qualifying intronic variants, whereas this variant is an in-frame deletion, regardless of its SpliceAI maximum delta 0.068.
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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