LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-25
Case ID: NM_000059.4_c.7908T_A_20260925_140528
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.7908T>A

BRCA2  · NP_000050.3:p.(Cys2636Ter)  · NM_000059.4
GRCh37: chr13:32936762 T>A  ·  GRCh38: chr13:32362625 T>A
Gene: BRCA2 Transcript: NM_000059.4
Final call
Pathogenic
PVS1 very strong PM5 strong (PTC) PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Cys2636Ter)
gnomAD AF
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 very strong: the ENIGMA exon 17 rule applies to this upstream BRCA2 protein-truncating variant.
2
PM5 strong: ENIGMA assigns the exon 17 PTC code PM5_Strong (PTC).
3
PP5 supporting: an exact-match ENIGMA expert-panel ClinVar classification is Pathogenic.
Final determination: ENIGMA BRCA2 Table 3 classifies a variant as Pathogenic when one Very Strong criterion and at least one Strong criterion are met; here these are PVS1 very strong and PM5 strong (PTC).
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: ENIGMA Table 4 assigns PVS1 to BRCA2 exon 17 PTCs, and p.Cys2636Ter truncates 783 of 3418 amino acids upstream of the terminal exon.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS1 N/A Not applicable: c.7908T>A is a nonsense PTC, whereas ENIGMA PS1 requires a pathogenic same-amino-acid or same-splicing comparison.
vcep_specifications_v1_2_2024_11_18
PS2 N/A Not applicable: ENIGMA explicitly prohibits PS2 for BRCA2 because de novo occurrences are not calibrated for these commonly occurring cancers.
cspec
PS3 Not assessed Not assessed: no calibrated damaging functional-assay result was found for c.7908T>A, p.Cys2636Ter, or p.C2636*.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4 Not assessed Not assessed: no variant-specific case-control OR, confidence interval, p-value, or qualifying affected/control counts were available for the PS4 OR >=4 threshold.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PM1 N/A Not applicable: residue 2636 lies within the DNA-binding domain, but ENIGMA PM1 is missense-domain evidence and this variant is a nonsense PTC.
vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not assessed Not assessed: the variant is absent from both required non-cancer gnomAD datasets, but the ENIGMA PM2 prerequisite of regional average read depth at least 25 is undocumented.
cspec gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM3 Not assessed Not assessed: no Fanconi Anemia phenotype, same-gene pathogenic co-variant, or verified phase is documented for PM3 application.
cspec
PM4 N/A Not applicable: ENIGMA explicitly says not to use PM4, and this variant is a nonsense PTC rather than an in-frame indel 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 17, which contains c.7908.
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: ENIGMA explicitly prohibits PM6 for BRCA2 because uncalibrated de novo occurrences cannot support this criterion.
cspec
PP1 Not assessed Not assessed: no variant-specific pedigree or quantitative segregation LR was available to compare with the PP1 threshold of LR >=2.08.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PP2 N/A Not applicable: ENIGMA marks PP2 not applicable, and this variant is a nonsense PTC rather than a missense change.
vcep_specifications_v1_2_2024_11_18
PP3 N/A Not applicable: the nonsense variant p.(Cys2636Ter) is outside the VCEP PP3 scope, which covers missense, in-frame, silent, or eligible intronic variants.
cspec
PP4 Not assessed Not assessed: the gene-specific clinical-history table has no c.7908T>A row, so no combined LR can be compared with the PP4 >=2.08 threshold.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331
PP5 Met Met, Supporting: exact ClinVar variation 52433 has an ENIGMA expert-panel Pathogenic classification, satisfying the requested PP5 rule.
clinvar cspec
BA1 Not met Not met: the variant is absent from the governing non-cancer gnomAD datasets, so no filter allele frequency exceeds the ENIGMA BA1 threshold of 0.1%.
cspec gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS1 Not met Not met: the variant is absent from both governing non-cancer gnomAD datasets, so its frequency does not reach the ENIGMA BS1 threshold of 0.01%.
cspec gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS2 Not assessed Not assessed: no individual-level homozygote, healthy-carrier, age, follow-up, or Fanconi Anemia phenotype data are available to assign ENIGMA BS2 points.
cspec gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS3 Not assessed Not assessed: no calibrated benign functional-assay result was found for c.7908T>A, p.Cys2636Ter, or p.C2636*.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4 Not assessed Not assessed: no variant-specific non-segregation data or quantitative LR was available to compare with the BS4 supporting threshold of LR <=0.48.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP1 N/A Not applicable: SpliceAI max delta 0.023 is low, but ENIGMA BP1 requires a silent, missense, or in-frame variant, not a nonsense PTC.
vcep_specifications_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: ENIGMA BRCA2 V1.2 explicitly prohibits BP2 and permits it only in the context of BS2.
cspec
BP3 N/A Not applicable: BP3 concerns in-frame indels in repetitive regions, whereas this variant is a nonsense substitution producing p.Cys2636Ter.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: the nonsense variant p.(Cys2636Ter) is outside the VCEP BP4 scope, which covers missense, in-frame, silent, or eligible intronic variants.
cspec
BP5 Not assessed Not assessed: no exact-variant clinical-history LR was available for comparison with the BP5 Supporting threshold LR <=0.48.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331
BP6 Not met Not met: exact ClinVar variation 52433 is Pathogenic by an ENIGMA expert panel, not Benign or Likely Benign for BP6.
clinvar cspec
BP7 N/A Not applicable: BP7 is restricted to synonymous or eligible intronic variants, whereas this variant is the nonsense change p.(Cys2636Ter).
cspec
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