LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-19
Case ID: NM_000059.4_c.9257G_C_20261019_180114
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.9257G>C

BRCA2  · NP_000050.3:p.(Gly3086Ala)  · NM_000059.4
GRCh37: chr13:32968826 G>C  ·  GRCh38: chr13:32394689 G>C
Gene: BRCA2 Transcript: NM_000059.4
Final call
Likely Benign
BS1 strong BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Gly3086Ala)
gnomAD AF
2.9766186604223822e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Likely Neutral
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BS1 Strong: the maximum non-cancer filter allele frequency is 0.00043582, above the ENIGMA threshold of 0.0001.
2
BP4 Supporting: BayesDel -0.0288497 and SpliceAI 0.011 meet the ENIGMA BRCA2 no-impact thresholds.
Final determination: Under ENIGMA BRCA2 VCEP Table 3, one Strong benign criterion plus one Supporting benign criterion yields Likely Benign.
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.9257G>C is a missense p.Gly3086Ala substitution, whereas ENIGMA PVS1 applies to specified null variants.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 PMID:31143303
PS1 Not assessed Not assessed: SpliceAI max delta 0.011 meets the <=0.1 requirement, but no qualifying pathogenic same-amino-acid reference variant was found.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 PMID:31143303
PS2 N/A Not applicable: the VCEP explicitly says to not use PS2 because de novo occurrences lack calibrated predictive information for BRCA1/2-related cancers.
cspec
PS3 Not assessed Not assessed: no qualifying calibrated protein-function result was found, while the available variant-specific assay was mRNA-only and showed no splicing abnormality.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:31143303
PS4 Not assessed Not assessed: no exact variant-level case-control p-value, OR, or confidence interval was available to test the ENIGMA PS4 thresholds.
cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM1 N/A Not applicable: the ENIGMA specification says PM1 is not to be used, even though residue 3086 lies in the DNA-binding region.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not met Not met: the variant is present in gnomAD v2.1 non-cancer exomes at AF 8.4938e-05 and gnomAD v3.1 non-cancer genomes at AF 2.7096e-05.
cspec gnomad_v2 gnomad_v4
PM3 Not met Not met: gnomAD maximum FAF is 0.00043457, exceeding the VCEP benign-evidence threshold of 0.0001, and no Fanconi-anemia proband with a same-gene co-occurring variant is documented.
cspec gnomad_v2 gnomad_v4
PM4 N/A Not applicable: PM4 is explicitly not used by ENIGMA, and p.Gly3086Ala is a missense substitution without a protein-length change.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: PM5 is not used for missense variants under ENIGMA and the variant is not a protein-termination-codon change.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM6 N/A Not applicable: the VCEP explicitly says to not use PM6 because de novo occurrences lack calibrated predictive information for BRCA1/2-related cancers.
cspec
PP1 Not assessed Not assessed: no variant-specific pedigree or quantitative segregation likelihood ratio was available to compare with the VCEP's PP1 threshold of LR ≥2.08:1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP2 N/A Not applicable: ENIGMA says PP2 is not to be used because BRCA2 has a high frequency of benign missense variants.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Not met Not met: BayesDel -0.0288497 is below the 0.30 PP3 threshold and SpliceAI 0.011 is below the 0.2 splice threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 bayesdel spliceai
PP4 Not assessed Not assessed: no exact combined clinical likelihood ratio was available to test the ENIGMA PP4 threshold of LR ≥2.08:1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5 N/A Not applicable: the ENIGMA BRCA2 specification explicitly says PP5 should not be used.
cspec vcep_specifications_v1_2_2024_11_18
BA1 Not met Not met: maximum non-cancer grpmax FAF was 0.00043582, below the ENIGMA BA1 threshold of 0.001.
cspec gnomad_v2 gnomad_v4
BS1 Met Met at strong: maximum non-cancer grpmax FAF was 0.00043582, exceeding the ENIGMA BS1 threshold of 0.0001.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: one gnomAD homozygote lacks the VCEP-required phenotyped-individual and age/follow-up data for BS2.
cspec gnomad_v2
BS3 Not assessed Not assessed: the only variant-specific assay was mRNA-only, showing no splicing abnormality but providing no calibrated evidence that the encoded protein is functionally benign.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:31143303
BS4 Not assessed Not assessed: no variant-specific pedigree or quantitative negative-segregation likelihood ratio was available to compare with the VCEP's BS4 threshold of LR ≤0.48:1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP1 N/A Not applicable: residue 3086 is inside the ENIGMA DNA-binding domain aa 2481-3186, whereas BP1 requires a variant outside that domain.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP2 N/A Not applicable: the VCEP explicitly says BP2 is not used and permits it only in the context of BS2.
cspec
BP3 N/A Not applicable: BP3 is explicitly not used by ENIGMA, and p.Gly3086Ala is not an in-frame deletion or insertion in a repeat region.
cspec vcep_specifications_v1_2_2024_11_18
BP4 Met Met, Supporting: BayesDel -0.0288497 is <=0.18 and SpliceAI 0.011 is <=0.1, satisfying both BRCA2 BP4 no-impact requirements.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 bayesdel spliceai PMID:31143303
BP5 Not assessed Not assessed: no exact combined clinical LR was available to test the ENIGMA BP5 operator LR ≤0.48:1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6 N/A Not applicable: the ENIGMA BRCA2 specification explicitly says BP6 should not be used.
cspec vcep_specifications_v1_2_2024_11_18
BP7 N/A Not applicable: BP7 covers silent or qualifying intronic variants, or missense variants outside domains, whereas p.Gly3086Ala is missense inside the DNA-binding domain.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
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