LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-09
Case ID: NM_007294.4_c.4331del_20261009_193238
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_007294.4:c.4331del

BRCA1  · NP_009225.1:p.(Asn1444IlefsTer12)  · NM_007294.4
GRCh37: chr17:41234446 AT>A  ·  GRCh38: chr17:43082429 AT>A
Gene: BRCA1 Transcript: NM_007294.4
Final call
Pathogenic
PVS1 very strong PM5 strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA1
Transcript
NM_007294.4
Protein
NP_009225.1:p.(Asn1444IlefsTer12)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PVS1 (very strong) is assigned for the exon E12(13) frameshift premature-termination variant.
2
Pathogenic: PM5 (strong) is assigned by ENIGMA Table 4 for a PTC in exon E12(13).
Final determination: Under ENIGMA BRCA1/2 Specifications v1.2 Table 3, one Very Strong pathogenic criterion plus one Strong pathogenic criterion yields Pathogenic.
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 Met Met, very strong: the exon E12(13) Table 4 row assigns PVS1 to coding PTC variants, and c.4331del creates p.Asn1444IlefsTer12 in a 1864-residue protein.
cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PS1 N/A Not applicable: c.4331del is a frameshift, whereas ENIGMA PS1 requires a same-protein missense change or precisely matching splice event.
cspec 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
PS2 N/A Not applicable: ENIGMA v1.2 prohibits PS2 because de novo occurrences are not calibrated for relatively common BRCA1/2-related cancers.
cspec
PS3 Not assessed Not assessed: no variant-specific calibrated assay result or pre-assigned PS3 code was found for c.4331del or p.Asn1444IlefsTer12.
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:11358863 PMID:12483515 PMID:12947386 PMID:20608970
PS4 Not assessed Not assessed: no case-control p-value, OR, or confidence interval is available for comparison with p-value <=0.05 and OR >=4.
cspec vcep_specifications_v1_2_2024_11_18
PM1 N/A Not applicable: residue 1444 is 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
PM2 N/A Not applicable: ENIGMA excludes PM2 for deletion variants, even though c.4331del was absent from the specified non-cancer gnomAD datasets.
cspec gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no documented Fanconi-anemia phenotype, same-gene pathogenic partner, affected-proband observation, or phase evidence was available to reach the ENIGMA PM3 point thresholds.
cspec
PM4 N/A Not applicable: ENIGMA does not use PM4, which is reserved for in-frame length changes or stop-loss variants, not this frameshift PTC.
cspec vcep_specifications_v1_2_2024_11_18
PM5 Met Met, strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA1 exon 12(13), where c.4331del creates a p.1455 termination.
vcep_specifications_table4_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
PM6 N/A Not applicable: ENIGMA v1.2 prohibits PM6 because assumed de novo occurrences are not calibrated for relatively common BRCA1/2-related cancers.
cspec
PP1 Not assessed Not assessed: no quantitative cosegregation LR or affected-family meioses are provided to compare with the ENIGMA PP1 supporting threshold of LR >=2.08:1.
cspec
PP2 N/A Not applicable: PP2 is restricted to missense variants, whereas c.4331del is a frameshift producing p.(Asn1444IlefsTer12).
cspec vcep_specifications_v1_2_2024_11_18
PP3 N/A Not applicable: c.4331del is a frameshift, outside ENIGMA PP3 scope, so the available SpliceAI max delta 0.007 is not evaluated.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP4 Not assessed Not assessed: no exact-variant combined clinical LR is available for comparison with the PP4 Supporting threshold LR >=2.08:1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 PMID:17924331
PP5 Not assessed Not assessed: ClinVar has no exact-variant expert-panel pathogenic or likely pathogenic classification, and ENIGMA marks PP5 as not for use.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
BA1 Not met Not met: the variant was absent from gnomAD v2.1 and v4.1, so no non-founder filter allele frequency exceeded the ENIGMA BA1 threshold of 0.001.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: the variant was absent from both specified non-cancer gnomAD datasets, giving frequency 0 below the ENIGMA BS1 Supporting threshold of 0.00002.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: no qualifying healthy-adult, homozygous, phase, age, follow-up, or Fanconi Anemia data were available for the ENIGMA BS2 point system.
cspec
BS3 Not assessed Not assessed: no variant-specific calibrated benign assay result or pre-assigned BS3 code was found for c.4331del or p.Asn1444IlefsTer12.
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:11358863 PMID:12483515 PMID:12947386 PMID:20608970
BS4 Not assessed Not assessed: no quantitative non-segregation LR or affected relatives lacking the variant are provided to compare with the ENIGMA BS4 supporting threshold of LR <=0.48:1.
cspec
BP1 N/A Not applicable: BP1 covers silent, missense, or in-frame changes, not the c.4331del frameshift despite SpliceAI max delta 0.007.
cspec spliceai vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP2 N/A Not applicable: the ENIGMA BRCA1/2 specification says BP2 is not used and permits it only as part of BS2, not as an independent criterion.
cspec
BP3 N/A Not applicable: ENIGMA does not use BP3, which is reserved for in-frame indels in functionless repeat regions, not this frameshift PTC.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: c.4331del is a frameshift, outside ENIGMA BP4 scope, so the available SpliceAI max delta 0.007 is not evaluated.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP5 Not assessed Not assessed: no exact-variant combined clinical LR is available for comparison with the BP5 Supporting interval LR <=0.48 and >0.23.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058 PMID:17924331
BP6 Not assessed Not assessed: ClinVar has no exact-variant expert-panel benign or likely benign classification, and ENIGMA marks BP6 as not for use.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
BP7 N/A Not applicable: c.4331del is a frameshift, not a synonymous or eligible intronic variant, so BP7 and SpliceAI max delta 0.007 are not evaluated.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
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