LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-14
Case ID: NM_000059.4_c.9396A_G_20261014_135112
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.9396A>G

BRCA2  · NP_000050.3:p.(Lys3132=)  · NM_000059.4
GRCh37: chr13:32968965 A>G  ·  GRCh38: chr13:32394828 A>G
Gene: BRCA2 Transcript: NM_000059.4
Final call
Likely Benign
BP4 supporting benign BP6 supporting benign BP7 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.(Lys3132=)
gnomAD AF
1.548804694488981e-05 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BP4 supporting benign: SpliceAI maximum delta 0.003 is below the ENIGMA threshold of 0.1.
2
BP6 supporting benign: exact ClinVar expert-panel classification is Likely benign.
3
BP7 supporting benign: synonymous variant with no predicted splice impact satisfies the ENIGMA BP7 rule alongside BP4.
Final determination: Under the ENIGMA BRCA2 v1.2 Table 3 point system, three supporting benign criteria contribute -3 points, which maps to Likely Benign in the -6 to -2 range.
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 Not applicable: c.9396A>G is synonymous, with SpliceAI max delta 0.003 and no qualifying null or canonical splice consequence for PVS1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 spliceai
PS1 N/A Not applicable: the variant is synonymous, and SpliceAI max delta 0.003 provides no predicted splice event for PS1 comparison.
cspec spliceai
PS2 N/A Not applicable: the ENIGMA VCEP explicitly prohibits PS2 for BRCA1/2 because de novo occurrences are not calibrated for these relatively common cancers.
cspec
PS3 Not assessed Not assessed: no variant-specific protein-function or combined mRNA/protein assay was found, and SpliceAI maximum delta 0.003 is not PS3 evidence.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
PS4 Not assessed Not assessed: no variant-specific case-control p-value, OR >=4, or confidence interval excluding 2.0 was available.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PM1 N/A Not applicable: ENIGMA explicitly prohibits PM1, despite residue 3132 lying within the stated DNA-binding interval aa 2481-3186.
cspec vcep_appendices_v1_2_2024_11_18
PM2 Not assessed Not assessed: required non-cancer absence is unknown, while all-comers gnomAD confirms presence at 3/251368 and 25/1614148 alleles.
cspec gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no Fanconi Anemia phenotype, pathogenic BRCA2 variant in trans, phase, or PM3 point-bearing proband observation is available.
cspec vcep_specifications_v1_2_2024_11_18
PM4 N/A Not applicable: the synonymous p.(Lys3132=) change causes no protein-length change, whereas ENIGMA PM4 is restricted to in-frame indels or stop-loss variants.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM5 N/A Not applicable: p.Lys3132= is synonymous, whereas ENIGMA PM5 is not used for missense and PM5 (PTC) requires a termination-codon variant.
cspec vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable: the ENIGMA VCEP explicitly prohibits PM6 for BRCA1/2 because uncalibrated de novo occurrences cannot support this criterion.
cspec
PP1 Not assessed Not assessed: no segregation observations or quantitative LR are available, so the ENIGMA PP1 thresholds of 2.08, 4.3, 18.7, and 350 cannot be applied.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PP2 N/A Not applicable: ENIGMA marks PP2 as Not Applicable, and the variant is synonymous rather than missense.
cspec
PP3 Not met Not met: SpliceAI maximum delta 0.003 is below the ENIGMA PP3 threshold of >=0.2 for synonymous variants.
cspec spliceai
PP4 Not assessed Not assessed: no exact-variant combined clinical LR was available for comparison with the PP4 supporting threshold LR >=2.08.
cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 vcep_pmid_17924331_easton_2007_ajhg vcep_pmid_31853058_li_2020_geneticsinmedicine
PP5 Not met Not met: the exact ClinVar expert-panel classification is Likely benign, whereas PP5 requires Pathogenic or Likely pathogenic.
clinvar cspec
BA1 Not assessed Not assessed: the VCEP-required non-cancer frequencies failed, so the BA1 threshold of FAF > 0.001 cannot be evaluated.
cspec gnomad_v2 gnomad_v4
BS1 Not assessed Not assessed: the VCEP-required non-cancer frequencies failed, so the BS1 FAF thresholds of >0.00002 to 0.0001 cannot be evaluated.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: gnomAD reports 0 homozygotes, but no healthy-adult observations or ENIGMA Table 8 point assignments are available for BS2.
cspec gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: no variant-specific benign protein-function or combined mRNA/protein assay was found, and SpliceAI maximum delta 0.003 cannot establish BS3.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BS4 Not assessed Not assessed: no affected-relative non-segregation data or quantitative LR are available, so the ENIGMA BS4 thresholds of 0.48, 0.23, 0.05, and 0.00285 cannot be applied.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP1 Not met Not met: SpliceAI max delta 0.003 is permissive, but residue 3132 lies inside the excluded DNA-binding domain aa 2481-3186.
cspec spliceai
BP2 N/A Not applicable: the ENIGMA VCEP explicitly says BP2 is not to be used and limits it to the context of BS2.
cspec vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: c.9396A>G is a synonymous single-nucleotide substitution, not an in-frame deletion or insertion required by the ENIGMA BP3 rule.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP4 Met Met, supporting: SpliceAI maximum delta 0.003 is below the ENIGMA BP4 threshold of <=0.1 for this synonymous variant in the DNA-binding domain.
cspec spliceai
BP5 Not assessed Not assessed: no exact-variant clinical LR was available for comparison with the BP5 supporting inequality LR <=0.48.
cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 vcep_pmid_17924331_easton_2007_ajhg vcep_pmid_31853058_li_2020_geneticsinmedicine
BP6 Met Met, Supporting: exact ClinVar expert-panel classification is Likely benign, satisfying the requested BP6 rule.
clinvar cspec
BP7 Met Met, supporting: the synonymous variant has SpliceAI maximum delta 0.003, satisfying BP4 and the ENIGMA BP7 requirement for silent variants.
cspec spliceai
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