LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-10
Case ID: NM_000059.4_c.7141_7147dup_20260910_130412
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.7141_7147dup

BRCA2  · NP_000050.3:p.(Tyr2383SerfsTer11)  · NM_000059.4
GRCh37: chr13:32929129 A>ATCCATTT  ·  GRCh38: chr13:32354992 A>ATCCATTT
Gene: BRCA2 Transcript: NM_000059.4
Final call
Pathogenic
PVS1 very strong PM5 strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Tyr2383SerfsTer11)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PVS1 (very strong) is met for the exon 14 frameshift premature termination codon p.(Tyr2383SerfsTer11).
2
Pathogenic: PM5 (strong) is met under ENIGMA Table 4 for a protein-termination codon in BRCA2 exon 14.
Final determination: Under ENIGMA BRCA2 VCEP Version 1.2 Table 3, one Very Strong pathogenic criterion combined with at least 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 at very strong: the BRCA2 exon 14 frameshift PTC p.(Tyr2383SerfsTer11) is pre-assigned PVS1 by ENIGMA Table 4 and lies before the c.9600 NMD boundary.
cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PS1 N/A Not applicable: PS1 requires a predicted missense substitution or matched splice event, and this is a frameshift (p.Tyr2383SerfsTer11) with SpliceAI max delta 0.014.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
PS2 N/A Not applicable: ENIGMA BRCA2 v1.2 Table 1 explicitly directs 'Do not use' for PS2, as de novo occurrences are not calibrated for BRCA2.
cspec vcep_specifications_v1_2_2024_11_18
PS3 Not met Not met: no variant-specific functional assay exists for c.7141_7147dup, and the governing ENIGMA Table 9 lists no PS3 entry for this allele.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:10570174 PMID:11239455 PMID:20878484 PMID:22193408 PMID:24312913
PS4 Not assessed Not assessed: no case-control dataset exists for this frameshift, and no declared PS4 table contains an entry for c.7141_7147dup (OR >= 4 required).
cspec clinvar vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 gnomad_v2 gnomad_v4
PM1 N/A Not applicable: ENIGMA BRCA2 v1.2 Table 1 and Appendix J Table 16 both mark PM1 as 'do not use'/N/A, and residue 2383 is outside both defined domains (aa 10-40, aa 2481-3186).
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 N/A Not applicable: the ENIGMA VCEP prohibits PM2 for insertion, deletion or delins variants, and this is a 7-bp duplication absent from gnomAD.
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 Anemia phenotype and no co-occurrent pathogenic BRCA2 allele in trans are reported, which the VCEP PM3_VariableWeight rule requires.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM4 N/A Not applicable: ENIGMA BRCA2 v1.2 lists PM4 as 'Do not use', and this frameshift produces a premature stop, not an in-frame protein length change.
cspec vcep_specifications_v1_2_2024_11_18
PM5 Met Met at Strong: ENIGMA Table 4 pre-assigns PM5_Strong (PTC) to BRCA2 exon 14 protein-termination variants, and this frameshift's stop codon falls in exon 14.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM6 N/A Not applicable: ENIGMA BRCA2 v1.2 Table 1 explicitly directs 'Do not use' for PM6, as de novo occurrences are not calibrated for BRCA2.
cspec vcep_specifications_v1_2_2024_11_18
PP1 Not assessed Not assessed: no pedigree or relative genotypes exist for this variant, so the ENIGMA-required quantitative co-segregation LR (PP1 threshold >= 2.08:1) cannot be computed.
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
PP2 N/A Not applicable: ENIGMA BRCA2 v1.2 marks PP2 'do not use' because missense change is not a common BRCA2 mechanism, and this variant is a frameshift, not missense.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP3 N/A Not applicable: PP3 covers missense, in-frame and splice-region variants, while c.7141_7147dup is a frameshift PTC (p.Tyr2383SerfsTer11), so its impact belongs to PVS1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP4 Not assessed Not assessed: no combined clinical likelihood ratio exists for this variant, and ENIGMA PP4 requires LR >= 2.08.
cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 vcep_pmid_17924331_easton_2007_ajhg PMID:31853058 PMID:17924331
PP5 N/A Not applicable: ENIGMA declares PP5 not applicable for BRCA2, and the variant has no ClinVar expert-panel classification (absent from ClinVar).
cspec clinvar
BA1 Not met Not met: the variant is absent from gnomAD v2.1/v4.1 and non-cancer subsets (FAF 0), far below the VCEP 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 met Not met: the variant is absent from gnomAD v2.1/v4.1 and non-cancer subsets (FAF 0), below the VCEP BS1 threshold of 0.0001.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS2 Not met Not met: no genotype-positive probands were reported, so zero Table 8 points accrued toward the >= 1 point required for BS2_Supporting.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS3 Not met Not met: no functional assay of c.7141_7147dup was found reporting retained function, and the governing ENIGMA Table 9 lists no BS3 entry for this allele.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:10570174 PMID:11239455
BS4 Not assessed Not assessed: no family segregation data exist for this variant, so the ENIGMA-required co-segregation LR (BS4 supporting <= 0.48:1) cannot be computed.
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
BP1 N/A Not applicable: ENIGMA BP1_Strong is limited to silent, missense or in-frame indels outside functional domains, and this is an out-of-frame 7-bp duplication.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: the ENIGMA v1.2 specification explicitly bars BP2 for BRCA2, allowing it only within the gene-specific BS2 co-occurrence framework.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP3 N/A Not applicable: ENIGMA BRCA2 v1.2 lists BP3 as 'Do not use', and this frameshift is not an in-frame insertion or deletion in a repeat region.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: BP4 covers missense, in-frame, silent and intronic variants, while c.7141_7147dup is a frameshift PTC, so its low SpliceAI score was not used.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP5 Not assessed Not assessed: no multifactorial clinical likelihood ratio exists for this variant, and ENIGMA BP5 requires LR <= 0.48.
cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 vcep_pmid_17924331_easton_2007_ajhg PMID:31853058 PMID:17924331
BP6 N/A Not applicable: ENIGMA declares BP6 not applicable for BRCA2, and the variant is absent from ClinVar with no expert-panel assertion.
cspec clinvar
BP7 N/A Not applicable: BP7 applies only to synonymous (or deep-intronic) variants, and c.7141_7147dup is a frameshift PTC (p.Tyr2383SerfsTer11).
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
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