LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-10
Case ID: NM_000059.4_c.8275del_retrydiag_20260910
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.8275del

BRCA2  · NP_000050.3:p.(Val2759TrpfsTer18)  · NM_000059.4
GRCh37: chr13:32937612 TG>T  ·  GRCh38: chr13:32363475 TG>T
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.(Val2759TrpfsTer18)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PVS1 (very strong) is met for the exon 18 frameshift premature-termination codon.
2
Pathogenic: PM5 (strong) is met under ENIGMA Table 4 for a premature-termination codon in exon 18.
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: the exon 18 frameshift c.8275del yields p.Val2759TrpfsTer18, and ENIGMA Table 4 assigns full PVS1 to BRCA2 exon 18 PTC variants.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 pvs1_gene_context
PS1 N/A Not applicable: the variant is a frameshift, whereas ENIGMA PS1 applies to an identical missense change or precisely matched splice event.
cspec vcep_specifications_v1_2_2024_11_18
PS2 N/A Not applicable: the ENIGMA BRCA2 VCEP explicitly prohibits PS2 because de novo occurrences are not calibrated for these relatively common cancers.
cspec
PS3 Not assessed Not assessed: no governing VCEP Table 9 assignment or validated assay result reports BRCA2 c.8275del or p.(Val2759TrpfsTer18).
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_specifications_table9_v1_2_2024_11_18 PMID:10570174 PMID:11239455 PMID:20878484 PMID:22193408 PMID:24312913
PS4 Not assessed Not assessed: no variant-specific case-control OR, p-value, or confidence interval was available to evaluate the ENIGMA OR ≥4 and p-value ≤0.05 requirements.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PM1 N/A Not applicable: ENIGMA designates PM1 as not applicable, and this variant is a frameshift rather than a domain-assessed missense alteration.
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, despite the variant being absent from gnomAD v2.1 and v3.1 non-cancer datasets.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM3 Not assessed Not assessed: no Fanconi-anemia phenotype, second BRCA2 pathogenic variant, affected-proband observation, or phase information is documented for the required PM3 point calculation.
cspec gnomad_v2 gnomad_v4
PM4 N/A Not applicable: c.8275del is a frameshift with a premature stop, while ENIGMA excludes PM4 and limits it to in-frame length changes or stop-loss variants.
cspec vcep_specifications_v1_2_2024_11_18
PM5 Met Met, strong: ENIGMA Table 4 assigns PM5 (PTC) strong to BRCA2 exon 18, where c.8275del produces a premature stop at p.2776.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable: the ENIGMA BRCA2 VCEP explicitly prohibits PM6 because uncalibrated de novo occurrences cannot provide validated evidence.
cspec
PP1 Not assessed Not assessed: no affected-relative segregation data or quantitative LR is available to compare with the PP1 threshold of LR >=2.08:1.
cspec
PP2 N/A Not applicable: ENIGMA excludes PP2 for BRCA2 because missense variants are not a common disease mechanism, and this variant is a frameshift.
cspec vcep_specifications_v1_2_2024_11_18
PP3 N/A Not applicable: c.8275del is a frameshift, outside ENIGMA's PP3 computational-evidence scope for missense, in-frame, or splice-region variants.
cspec
PP4 Not assessed Not assessed: no exact-variant combined clinical LR was found to compare with the ENIGMA PP4 supporting threshold of LR ≥2.08.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5 N/A Not applicable: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic assertion for c.8275del.
clinvar cspec
BA1 Not met Not met: the variant was absent from the specified gnomAD datasets, so no filter allele frequency exceeded the ENIGMA BA1 threshold of 0.001.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS1 Not met Not met: the variant was absent from the specified gnomAD datasets, so no filter allele frequency exceeded the ENIGMA BS1 threshold of 0.0001.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS2 Not assessed Not assessed: no qualifying phenotyped individual, homozygote, trans co-occurrence, phase, or age-at-follow-up evidence was provided for the ENIGMA BS2 point system.
cspec vcep_appendices_v1_2_2024_11_18
BS3 Not assessed Not assessed: no governing VCEP Table 9 assignment or validated benign assay result reports BRCA2 c.8275del or p.(Val2759TrpfsTer18).
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_specifications_table9_v1_2_2024_11_18 PMID:10570174 PMID:11239455 PMID:20878484 PMID:22193408 PMID:24312913
BS4 Not assessed Not assessed: no affected-family non-segregation data or quantitative LR is available to compare with the BS4 threshold of LR <=0.48.
cspec
BP1 N/A Not applicable: BP1 requires a silent, missense, or in-frame indel outside a domain, but c.8275del is a frameshift despite SpliceAI 0.095.
cspec spliceai vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP2 N/A Not applicable: ENIGMA BRCA2 explicitly does not use BP2 independently and restricts it to the context of BS2.
cspec
BP3 N/A Not applicable: c.8275del is a premature-termination frameshift, whereas ENIGMA excludes BP3 and limits it to in-frame changes in repetitive regions without known function.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: c.8275del is a frameshift, outside ENIGMA's BP4 computational-evidence scope for missense, silent, or qualifying intronic variants.
cspec
BP5 Not assessed Not assessed: no exact-variant combined clinical LR was available to evaluate BP5's required LR ≤0.48 comparison.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331
BP6 N/A Not applicable: ClinVar has no exact-variant expert-panel Benign or Likely benign assertion for c.8275del.
clinvar cspec
BP7 N/A Not applicable: c.8275del is a frameshift, whereas ENIGMA's BP7 scope is limited to synonymous or qualifying intronic variants.
cspec
Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.