LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-10
Case ID: NM_000059.4_7141_7147dup_20260910_112545
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:7141_7147dup

BRCA2  ·   · 
GRCh37: None  ·  GRCh38: None
Gene: BRCA2 Transcript:
Final call
Pathogenic
PVS1 very strong PM5 strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
Protein
gnomAD AF
ClinVar
None
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PVS1 (very strong) is met for the exon 15 frameshift premature-termination codon expected to undergo nonsense-mediated decay.
2
Pathogenic: PM5 (strong) is met under ENIGMA Table 4 for a premature-termination codon in exon 14.
Final determination: Under ENIGMA BRCA2 VCEP Version 1.2 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: exon-15 frameshift p.(Tyr2383SerfsTer11) truncates the predicted product at residue 2393 of 3419 and is expected to undergo NMD.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS1 N/A Not applicable: c.7141_7147dup produces p.(Tyr2383SerfsTer11), not a missense substitution or precisely matching splice event eligible for PS1.
cspec vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS2 N/A Not applicable: ENIGMA explicitly prohibits PS2 because de novo occurrences lack calibrated predictive capacity for BRCA2-related cancers.
cspec
PS3 Not assessed Not assessed: no variant-specific calibrated functional assay result for c.7141_7147dup was found in the governing ENIGMA sources or case evidence.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4 Not assessed Not assessed: no variant-specific case-control p-value, OR, or confidence interval was available to evaluate the PS4 requirements p-value <=0.05 and OR >=4.
cspec vcep_supplementarytables_v1_2_2024_11_18
PM1 N/A Not applicable: the frameshift begins at Tyr2383, outside ENIGMA BRCA2 domains aa 10-40 and aa 2481-3186, with no authoritative domain-table entry.
cspec vcep_appendices_v1_2_2024_11_18
PM2 N/A Not applicable: ENIGMA explicitly excludes insertion, deletion, and delins variants from PM2.
cspec
PM3 Not assessed Not assessed: no Fanconi-anemia phenotype, chromosome-breakage result, or pathogenic BRCA2 co-occurring variant with phase information is documented for this duplication.
vcep_specifications_v1_2_2024_11_18
PM4 N/A Not applicable: ENIGMA v1.2 explicitly excludes PM4, and this variant is a frameshift null variant rather than an in-frame or stop-loss change.
cspec vcep_specifications_v1_2_2024_11_18
PM5 Met Met, Strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 14, where c.7141_7147dup creates p.(Tyr2383SerfsTer11).
cspec vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable: ENIGMA explicitly prohibits PM6 because de novo occurrences lack calibrated predictive capacity for BRCA2-related cancers.
cspec
PP1 Not assessed Not assessed: no affected-relative segregation data or quantitative likelihood ratio was available to reach the ENIGMA PP1 threshold of LR ≥2.08:1.
cspec
PP2 N/A Not applicable: ENIGMA explicitly marks PP2 as not applicable, and this variant is a frameshift duplication rather than a missense change.
cspec
PP3 N/A Not applicable: c.7141_7147dup creates p.(Tyr2383SerfsTer11), a frameshift outside PP3's missense, in-frame, silent, and intronic/splice-region scope.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_pmid_22505045_houdayer_2012_hummutat
PP4 Not assessed Not assessed: no variant-specific combined clinical LR was available for comparison with the PP4 Supporting threshold LR >=2.08.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331
PP5 Not assessed Not assessed: no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification was available to trigger PP5.
cspec
BA1 Not assessed Not assessed: no variant-specific gnomAD FAF, coverage, or quality-filter data are available to compare with the VCEP threshold of >0.001.
cspec
BS1 Not assessed Not assessed: no variant-specific gnomAD FAF is available to compare with the VCEP BS1 thresholds of >0.00002 to >0.0001.
cspec
BS2 Not assessed Not assessed: no healthy-adult genotype/co-occurrence or Fanconi-anemia phenotype data are available to assign the VCEP point score.
cspec
BS3 Not assessed Not assessed: no variant-specific calibrated benign functional assay result for c.7141_7147dup was found in the governing ENIGMA sources or case evidence.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4 Not assessed Not assessed: no affected-relative non-segregation data or quantitative likelihood ratio was available to reach the ENIGMA BS4 threshold of LR ≤0.48:1.
cspec
BP1 N/A Not applicable: BP1 requires a silent, missense, or in-frame variant, whereas c.7141_7147dup is a frameshift duplication producing p.(Tyr2383SerfsTer11).
cspec
BP2 N/A Not applicable: the ENIGMA BRCA2 specification explicitly excludes BP2 and limits related co-observation assessment to BS2.
vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: ENIGMA v1.2 excludes BP3, which applies only to in-frame repeat-region insertions/deletions without known function.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: c.7141_7147dup creates p.(Tyr2383SerfsTer11), a frameshift outside BP4's missense, in-frame, silent, and intronic/splice-region scope.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_pmid_22505045_houdayer_2012_hummutat
BP5 Not assessed Not assessed: no variant-specific clinical LR was available for the BP5 Supporting inequality LR <=0.48.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331
BP6 Not assessed Not assessed: no exact-variant ClinVar expert-panel Benign or Likely benign classification was available to trigger BP6.
cspec
BP7 N/A Not applicable: c.7141_7147dup creates p.(Tyr2383SerfsTer11), a frameshift rather than a synonymous variant required for BP7.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_pmid_22505045_houdayer_2012_hummutat
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