LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-23
Case ID: NM_000059.3_c.10043del_20261023_174556
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.3:c.10043del

BRCA2  · NP_000050.2:p.(Asn3348IlefsTer35)  · NM_000059.3
GRCh37: chr13:32972690 TA>T  ·  GRCh38: chr13:32398553 TA>T
Gene: BRCA2 Transcript: NM_000059.3
Final call
VUS
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.3
Protein
NP_000050.2:p.(Asn3348IlefsTer35)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS: no pathogenic or benign criterion is met, so no ENIGMA Table 3 combining rule on either side is satisfied.
2
PVS1 (not applicable): ENIGMA Table 4 assigns no PVS1 weight to exon 27 truncations terminating after p.Glu3309, and this frameshift stops near codon 3382.
3
PM2 (not applicable): ENIGMA v1.2 excludes PM2 for deletion variants, so absence from gnomAD cannot be scored.
4
BA1/BS1 (not met): the variant is absent from gnomAD, well below the >0.001 and >0.0001 frequency thresholds.
5
PS3/BS3 (not met): no calibrated functional assay of c.10043del exists in Specifications Table 9 or Supplementary Table 4.
Final determination: Under ENIGMA BRCA2 v1.2 Table 3 (adapted ACMG/AMP 2015 Table 5), with no pathogenic and no benign criterion met, no combining rule on either side is satisfied and the variant defaults to Uncertain Significance.
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: BRCA2 Table 4 assigns PVS1_N/A to exon 27 termination codons after p.E3309, and this frameshift stops near codon 3382.
cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:10570174
PS1 N/A Not applicable: PS1 is restricted to missense substitutions or splice-equivalent variants, and this frameshift has no amino-acid-change comparator at residue 3348.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 clinvar spliceai
PS2 N/A Not applicable: the ENIGMA BRCA2 v1.2 specification explicitly marks PS2 'Do not use' because BRCA1/2 cancers are common, so no de novo weight can be applied.
cspec vcep_specifications_v1_2_2024_11_18
PS3 Not met Not met: no calibrated functional assay reports this variant, and Specifications Table 9 carries no row for c.10043del or p.Asn3348IlefsTer35.
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 PMID:10570174 PMID:11239455 PMID:20878484
PS4 Not assessed Not assessed: ENIGMA PS4 requires a case-control OR >=4 with lower CI excluding 2.0, and no case-control data exist for c.10043del.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 clinvar gnomad_v2 gnomad_v4
PM1 N/A Not applicable: ENIGMA v1.2 lists PM1 as 'Do not use' (its content folded into PP3/BP4), and residue 3348 lies outside both declared domains (PALB2 aa 10-40, DBD aa 2481-3186).
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 oncokb PMID:10570174
PM2 N/A Not applicable: PM2 is excluded for insertion/deletion variants, and this is a 1-bp frameshift deletion.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
PM3 Not met Not met: no Fanconi Anaemia proband and no co-occurrent BRCA2 P/LP variant is reported, so zero of the >=1 PM3 point threshold can be assigned.
cspec vcep_specifications_v1_2_2024_11_18 clinvar PMID:10570174 PMID:11239455 PMID:20878484 PMID:22193408 PMID:24312913
PM4 N/A Not applicable: the VCEP does not use PM4 for BRCA2, and this frameshift is neither an in-frame indel nor a stop-loss variant.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: Table 4 pre-assigns PM5_N/A for BRCA2 exon 27 PTCs terminating after p.E3309, and this frameshift's termination codon is p.Ter3382.
cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PM6 N/A Not applicable: the ENIGMA BRCA2 v1.2 specification marks PM6 'Do not use', so unconfirmed de novo evidence cannot be scored for this variant.
cspec vcep_specifications_v1_2_2024_11_18
PP1 Not assessed Not assessed: no co-segregation LR (PP1 needs >=2.08:1) exists for this variant in ClinVar, the five papers, or the ENIGMA/Parsons tables.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 clinvar PMID:20878484 PMID:10570174
PP2 N/A Not applicable: ENIGMA v1.2 marks PP2 'Do not use' (BRCA2 has a high frequency of benign missense variants), and this variant is a frameshift, not missense.
cspec vcep_specifications_v1_2_2024_11_18
PP3 N/A Not applicable: PP3 covers only missense/in-frame, silent or intronic variants, and c.10043del is a frameshift (p.N3348Ifs*35) assessed under PVS1.
cspec spliceai vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP4 Not assessed Not assessed: ENIGMA PP4 requires a combined multifactorial LR >=2.08, and no clinical-history LR exists for c.10043del in the BRCA2 tables.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_humu_40_1557_s001 PMID:31131967 vcep_supplementarytables_v1_2_2024_11_18
PP5 N/A Not applicable: ENIGMA BRCA2 v1.2 specifies PP5 must not be used, and the variant has no ClinVar record in any case.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
BA1 Not met Not met: filter allele frequency is 0 in gnomAD v2.1 non-cancer exomes and v4.1, versus the >0.001 BA1 threshold.
cspec gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS1 Not met Not met: filter allele frequency is 0 in gnomAD v2.1 non-cancer exomes and v4.1, versus the >0.00002 BS1_Supporting floor.
cspec gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS2 Not met Not met: no proband-level in-trans or homozygous observation yields any of the >=4 BS2 points required.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS3 Not met Not met: no assay reports c.10043del, although Table 9 assigns BS3 Strong to neighbouring exon 27 truncations c.9945del and c.10184del.
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 PMID:10570174 PMID:11239455 PMID:20878484 PMID:22193408 PMID:24312913
BS4 Not assessed Not assessed: no quantitative non-segregation LR (BS4 needs <=0.48:1) exists for this variant in ClinVar, the five papers, or the ENIGMA/Parsons tables.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 clinvar
BP1 N/A Not applicable: BP1_Strong covers only silent, missense or in-frame variants with SpliceAI <=0.1, and this is a frameshift with SpliceAI max delta 0.205.
cspec vcep_specifications_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: the ENIGMA BRCA2 v1.2 specification marks BP2 'Do not use', delegating allelic-phase evidence to the BS2 point system.
cspec vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: the VCEP does not use BP3 for BRCA2, and a frameshift is not an in-frame indel in a repetitive region.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: BP4 covers missense/in-frame, silent or intronic variants, and c.10043del is a truncating frameshift whose SpliceAI delta (0.205) also fails the <=0.1 rule.
cspec spliceai vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BP5 Not assessed Not assessed: ENIGMA BP5 requires a combined multifactorial LR <=0.48, and no such LR exists for c.10043del in the BRCA2 tables.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_humu_40_1557_s001 PMID:31131967 vcep_supplementarytables_v1_2_2024_11_18 PMID:10570174
BP6 N/A Not applicable: ENIGMA BRCA2 v1.2 specifies BP6 must not be used, and the variant has no ClinVar record in any case.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
BP7 N/A Not applicable: BP7 covers silent, intronic or missense/in-frame variants (RNA assay or BP4 met), and c.10043del is a frameshift with no mRNA assay available.
cspec spliceai vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:22505045
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