LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-21
Case ID: NM_000059.4_c.9934A_G_20260921_143936
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.9934A>G

BRCA2  · NP_000050.3:p.(Ile3312Val)  · NM_000059.4
GRCh37: chr13:32972584 A>G  ·  GRCh38: chr13:32398447 A>G
Gene: BRCA2 Transcript: NM_000059.4
Final call
Likely Benign
BP1 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.(Ile3312Val)
gnomAD AF
1.3628670758571815e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BP1 strong because residue 3312 lies outside the defined BRCA2 functional domains and SpliceAI max delta is 0.014.
2
Likely Benign: BP4 supporting because REVEL is 0.017, below the benign threshold for missense variants.
Final determination: The ENIGMA BRCA2 V1.2 Table 3 framework assigns Likely Benign when one Strong benign criterion and one Supporting benign criterion are met; BP1 Strong plus BP4 Supporting satisfies this rule.
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.9934A>G is missense p.(Ile3312Val), not a VCEP-defined null variant eligible 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
PS1 Not assessed Not assessed: no governing-VCEP entry or established pathogenic comparator for p.Ile3312Val was identified in the searched files.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:33773534
PS2 N/A Not applicable: ENIGMA explicitly prohibits PS2 for BRCA2 because de novo cancer occurrences lack calibrated predictive value.
cspec vcep_specifications_v1_2_2024_11_18
PS3 Not assessed Not assessed: no variant-specific protein-function assay or pre-assigned PS3 code was found in the governing ENIGMA materials.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:33773534
PS4 Not assessed Not assessed: no exact-variant case-control odds ratio, p-value, and confidence interval were available for PS4 (p-value <=0.05 and OR >=4).
cspec vcep_supplementarytables_v1_2_2024_11_18 PMID:33773534
PM1 N/A Not applicable: residue 3312 lies outside ENIGMA's BRCA2 critical domains aa 10-40 and aa 2481-3186, and PM1 is explicitly N/A.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not assessed Not assessed: required non-cancer absence and depth data are unavailable; all-comers gnomAD reports 4/251266 alleles in v2.1 and 22/1614244 in v4.1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: the exact-variant report documents heterozygosity but no Fanconi-anemia phenotype, second pathogenic BRCA2 variant, or phase needed for ENIGMA PM3 points.
cspec PMID:33773534
PM4 N/A Not applicable: p.(Ile3312Val) is a single-amino-acid substitution with no in-frame length change or stop-loss consequence.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM5 N/A Not applicable: p.Ile3312Val is missense, whereas ENIGMA PM5 is restricted to protein-termination-codon variants.
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: ENIGMA explicitly prohibits PM6 because uncalibrated de novo occurrences do not provide usable BRCA2 evidence.
cspec vcep_specifications_v1_2_2024_11_18
PP1 Not assessed Not assessed: no segregation LR or tested affected relatives were reported, so the ENIGMA PP1 threshold of LR >=2.08 cannot be evaluated.
cspec vcep_specifications_v1_2_2024_11_18 PMID:33773534
PP2 N/A Not applicable: the governing ENIGMA BRCA2 V1.2 criterion table explicitly marks PP2 as not applicable.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Not met Not met: REVEL 0.017 is below the PP3 supporting threshold of 0.644 for missense variants.
cspec revel
PP4 Not met Not met: exact-variant clinical-history LR 0.7815407011846 >= 2.08? no, so it does not reach the ENIGMA PP4 Supporting threshold.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5 Not met Not met: ClinVar has zero exact-variant expert-panel submissions, and no expert-panel Pathogenic or Likely pathogenic classification is present.
clinvar
BA1 Not assessed Not assessed: required non-cancer FAF data are unavailable; available all-comers group-max FAF values were 7.02e-06 and 8.78e-06 versus the >0.001 BA1 threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS1 Not assessed Not assessed: required non-cancer FAF data are unavailable; available all-comers group-max FAF values were 7.02e-06 and 8.78e-06 versus the >0.00002 BS1 threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: gnomAD reports 0 homozygotes, but no phenotype-qualified biallelic observations or ENIGMA BS2 point assignments are available.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: no variant-specific protein-function assay or pre-assigned BS3 code was found in the governing ENIGMA materials.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:33773534
BS4 Not assessed Not assessed: no non-segregation LR or tested discordant affected relatives were reported, so the ENIGMA BS4 threshold of LR <=0.48 cannot be evaluated.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:33773534
BP1 Met Met at Strong: residue 3312 is outside ENIGMA domains aa 10-40 and aa 2481-3186, with SpliceAI max delta 0.014 <=0.1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: ENIGMA explicitly excludes BP2 for BRCA2 and permits it only in the context of BS2.
cspec
BP3 N/A Not applicable: c.9934A>G is a missense SNV, not an in-frame insertion or deletion in a repetitive region.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
BP4 Met Met at supporting strength: REVEL 0.017 is below the BP4 supporting threshold of 0.29 for missense variants.
cspec revel
BP5 Not met Not met: exact-variant clinical-history LR 0.7815407011846 <= 0.48? no, so it does not reach the ENIGMA BP5 Supporting threshold.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6 Not met Not met: ClinVar has zero exact-variant expert-panel submissions, so no expert-panel Benign or Likely benign classification supports BP6.
clinvar
BP7 N/A Not applicable: c.9934A>G is missense, whereas BP7 applies only to synonymous 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.