LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-21
Case ID: NM_000059.4_c.8386C_T_20260721_184515
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.8386C>T

BRCA2  · NP_000050.3:p.(Pro2796Ser)  · NM_000059.4
GRCh37: chr13:32944593 C>T  ·  GRCh38: chr13:32370456 C>T
Gene: BRCA2 Transcript: NM_000059.4
Final call
VUS
BP5 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Pro2796Ser)
gnomAD AF
1.7348633175543383e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
Final determination: Under ENIGMA BRCA2 v1.2 Table 3, a single Supporting benign criterion (BP5) with zero other met criteria matches no Likely Benign, Benign, Likely Pathogenic, or Pathogenic combination rule and 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 PVS1 is not applicable for missense variants under ENIGMA BRCA2 v1.2 specifications. PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon deletions). NM_000059.4:c.8386C>T is a missense substitution (p.Pro2796Ser).
cspec vcep_specifications_table4_v1_2_2024_11_18
PS1 Not met No previously classified pathogenic missense variant at codon 2796 has been identified. ENIGMA PS1 requires a same-amino-acid change as a previously classified pathogenic variant, or same predicted splicing impact as a classified pathogenic variant. No comparator variant at this codon was found.
cspec clinvar
PS2 N/A ENIGMA BRCA2 v1.2 specification marks PS2 as Not Applicable.
cspec
PS3 Not met NM_000059.4:c.8386C>T is not listed in ENIGMA Specifications Table 9 (curated BRCA2 functional assay results). No calibrated mammalian functional studies demonstrating a damaging effect on protein function are available for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.
vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 oncokb
PS4 Not assessed No case-control data meeting ENIGMA PS4 thresholds (p ≤ 0.05 and OR ≥ 4) are available for this variant. No case-control studies specific to NM_000059.4:c.8386C>T were identified in the literature.
cspec
PS5 N/A Skipped per adjudication instructions — trivially not applicable.
PM1 N/A ENIGMA BRCA2 v1.2 specification explicitly marks PM1 as Not Applicable for BRCA2 variants. Domain-level assessment is instead captured through PP3/BP4/BP1 bioinformatic rules based on location within the DNA binding domain (aa 2481-3186).
cspec
PM2 Not met Under ENIGMA BRCA2 v1.2, PM2 (Supporting only) requires absence from controls in gnomAD outbred populations. NM_000059.4:c.8386C>T is present in gnomAD v2.1 (4/251,442 alleles; grpmax FAF = 1.122e-05) and gnomAD v4.1 (28/1,613,960 alleles). The variant is not absent from population controls.
cspec gnomad_v2 gnomad_v4
PM5 N/A ENIGMA BRCA2 v1.2 repurposes PM5 exclusively for protein termination codon (PTC) variants in exons where a proven pathogenic PTC variant has been seen (PM5_PTC). NM_000059.4:c.8386C>T is a missense variant (p.Pro2796Ser), not a PTC/nonsense variant. Classic same-residue missense PM5 is not applicable under this VCEP framework. PM5_N/A is not assigned to exon 19 in Specifications Table 4, but PM5_PTC applies only to truncating variants.
cspec vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A ENIGMA BRCA2 v1.2 specification marks PM6 as Not Applicable.
cspec
PP1 Not assessed No co-segregation data are available for quantitative analysis. ENIGMA PP1 requires a likelihood ratio from co-segregation analysis with LR ≥ 2.08:1 (Supporting) or higher. No family segregation studies for NM_000059.4:c.8386C>T were identified.
cspec
PP2 N/A ENIGMA BRCA2 v1.2 specification marks PP2 as Not Applicable.
cspec
PP3 Not met Although p.Pro2796Ser lies within the BRCA2 DNA binding domain (aa 2481-3186), neither ENIGMA PP3 condition is satisfied: BayesDel no-AF score is -0.202329 (threshold ≥ 0.30 not met) and SpliceAI max delta is 0.16 (threshold ≥ 0.2 not met). No predicted impact on protein function or splicing by ENIGMA bioinformatic thresholds.
cspec bayesdel revel spliceai
PP4 Not met ENIGMA PP4 requires a combined LR ≥ 2.08:1 toward pathogenicity from multifactorial likelihood clinical data. The combined multifactorial LR from Parsons et al. 2019 (PMID:31131967) for NM_000059.4:c.8386C>T is 0.123, which is in the benign direction and well below the PP4 Supporting threshold. The variant is not present in the Li et al. 2020 clinical history LR dataset.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PP5 N/A ENIGMA BRCA2 v1.2 specification marks PP5 as Not Applicable for BRCA2 variants.
cspec
BA1 Not met ENIGMA BA1 (Stand Alone) requires filter allele frequency (FAF) > 0.1% (0.001) in gnomAD. The grpmax FAF for NM_000059.4:c.8386C>T is 1.122e-05 (0.00112%), far below the BA1 threshold. The variant is too rare in population databases to meet BA1.
cspec gnomad_v2
BS1 Not met ENIGMA BS1 Strong requires FAF > 0.01% (0.0001); BS1 Supporting requires FAF > 0.002% (0.00002). The grpmax FAF for NM_000059.4:c.8386C>T is 1.122e-05 (0.00112%), which is below even the Supporting threshold of 0.002%. The variant is too rare in population databases to meet BS1 at any strength.
cspec gnomad_v2
BS2 Not assessed ENIGMA BS2 requires proband-level assessment for absence of Fanconi Anemia phenotype features, scored per Specifications Table 8. No proband clinical phenotype data are available for this adjudication.
cspec
BS3 Not met NM_000059.4:c.8386C>T is not listed in ENIGMA Specifications Table 9 (curated functional assay results). No calibrated mammalian functional studies demonstrating no damaging effect on protein function are available. The Houdayer et al. 2012 (PMID:22505045) splicing assay showed no splicing aberration, but this is mRNA-level evidence only and does not satisfy BS3, which requires protein-level or combined mRNA+protein functional data under ENIGMA v1.2.
vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4 Not assessed ENIGMA BS4 requires a quantitative co-segregation analysis with LR ≤ 0.48:1 toward benign. No family segregation data are available for NM_000059.4:c.8386C>T.
cspec
BP1 Not met ENIGMA BP1 Strong requires a missense variant located OUTSIDE a clinically important functional domain AND no splicing predicted (SpliceAI ≤ 0.1). p.Pro2796Ser is located within the BRCA2 DNA binding domain (aa 2481-3186), and SpliceAI delta is 0.16 (> 0.1 threshold). Both conditions fail.
cspec spliceai
BP2 N/A ENIGMA BRCA2 v1.2 specification marks BP2 as Not Applicable.
cspec
BP4 Not met ENIGMA BP4 requires BOTH BayesDel no-AF ≤ 0.18 AND SpliceAI ≤ 0.1 for missense variants inside a clinically important functional domain. Although BayesDel no-AF (-0.202329, ≤ 0.18) is met and the variant lies within the DNA binding domain, SpliceAI max delta is 0.16, which exceeds the 0.1 threshold. BP4 is not met.
cspec bayesdel spliceai
BP5 Met ENIGMA BP5 Supporting applies when the combined likelihood ratio from multifactorial likelihood clinical data is ≤ 0.48:1. The combined LR from Parsons et al. 2019 (PMID:31131967) multifactorial analysis for NM_000059.4:c.8386C>T is 0.123, with a posterior probability of pathogenicity of 0.0038 and IARC class 2 (Likely Benign). The combined LR of 0.123 supports BP5 at Supporting strength. The combined LR incorporates co-occurrence, family history, pathology, and case-control likelihood components.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP6 N/A ENIGMA BRCA2 v1.2 specification marks BP6 as Not Applicable.
cspec
BP7 Not met ENIGMA BP7 Strong (RNA) for missense variants inside a clinically important functional domain requires BS3 to be met first. BS3 is not met for this variant. BP7 Supporting applies only to silent variants inside functional domains (if BP4 met) or intronic variants outside donor/acceptor positions. NM_000059.4:c.8386C>T is a missense variant and does not meet any BP7 rule condition. The Houdayer et al. 2012 splicing assay showed no splicing aberration, but this mRNA-only data does not independently qualify for BP7 under ENIGMA v1.2 rules for missense variants inside functional domains.
cspec vcep_supplementarytables_v1_2_2024_11_18
BP3 N/A Skipped per adjudication instructions — trivially not applicable.
PM3 N/A Skipped per adjudication instructions — trivially not applicable.
PM4 N/A Skipped per adjudication instructions — trivially not applicable.
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