LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-14
Case ID: NM_000059.4_c.3941A_G_20260914_195726
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.3941A>G

BRCA2  · NP_000050.3:p.(Lys1314Arg)  · NM_000059.4
GRCh37: chr13:32912433 A>G  ·  GRCh38: chr13:32338296 A>G
Gene: BRCA2 Transcript: NM_000059.4
Final call
Likely Benign
BP1 strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Lys1314Arg)
gnomAD AF
2.5333034403527373e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BP1 Strong is supported by the residue being outside critical BRCA2 domains and SpliceAI maximum delta of 0.001.
Final determination: Under ENIGMA BRCA2 Version 1.2 Table 3, a single Strong (Benign) criterion yields Likely Benign when it is supported by multiple evidence types.
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 Not met Not met: c.3941A>G is a missense variant, whereas ENIGMA PVS1 is restricted to null variants such as nonsense, frameshift, or canonical splice changes.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 PMID:16683254
PS1 Not met Not met: the exact variant was reported once as unclassified, with no pathogenic same-amino-acid comparator identified under the ENIGMA PS1 rule.
cspec PMID:16683254
PS2 N/A Not applicable: ENIGMA VCEP explicitly prohibits PS2 because de novo occurrence has not been calibrated for BRCA1/2-related cancers.
cspec
PS3 Not assessed Not assessed: no VCEP Table 9 entry or validated damaging protein assay was found for c.3941A>G; the reported paper labels its effect unknown.
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 PMID:16683254
PS4 Not assessed Not assessed: no variant-specific case-control OR, p-value, or confidence interval was available to evaluate the PS4 thresholds p-value <=0.05 and OR >=4.
cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:16683254
PM1 N/A Not applicable: ENIGMA explicitly prohibits PM1 for BRCA2, and Lys1314 lies outside its listed critical domains.
cspec
PM2 Not met Not met: the variant is observed once in gnomAD v2.1 non-cancer exomes (1/208114), so it is not absent from both required control datasets.
cspec vcep_appendices_v1_2_2024_11_18 gnomad_v2
PM3 Not assessed Not assessed: one family report lacks the VCEP-required Fanconi-anemia phenotype and pathogenic BRCA2 co-occurrence or phase information.
cspec PMID:16683254
PM4 N/A Not applicable: ENIGMA says do not use PM4, and c.3941A>G is a missense substitution with no protein-length change.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: ENIGMA restricts PM5 to PTC logic, whereas p.Lys1314Arg is a missense variant and no VCEP entry was found.
cspec vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable: ENIGMA VCEP explicitly prohibits PM6 because de novo occurrence has not been calibrated for BRCA1/2-related cancers.
cspec PMID:16683254
PP1 Not assessed Not assessed: no affected-relative segregation data or quantitative LR is available, and the ENIGMA PP1 supporting threshold is LR ≥2.08:1.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18 PMID:16683254
PP2 N/A Not applicable: ENIGMA prohibits PP2 for BRCA2 because the gene has a high frequency of benign missense variation.
cspec
PP3 Not met Not met: SpliceAI maximum delta 0.001 is below the ENIGMA PP3 threshold of >=0.2, and BayesDel -0.521046 is below the >=0.30 protein-impact threshold.
cspec spliceai bayesdel revel
PP4 Not assessed Not assessed: no exact-variant combined clinical LR was available to compare with the PP4 Supporting threshold LR >=2.08.
cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PP5 N/A Not applicable: the VCEP says not to use PP5, and ClinVar has zero expert-panel submissions for this exact variant.
cspec clinvar
BA1 Not met Not met: the highest reported population frequency is 2.77346e-05, far below the ENIGMA BA1 threshold of 0.001.
cspec gnomad_v2 gnomad_v4
BS1 Not assessed Not assessed: non-cancer allele frequency reaches 2.77346e-05, but the VCEP-required filter allele frequency is unavailable.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: gnomAD shows zero homozygotes, but no eligible healthy-adult observation or VCEP Table 8 point assignment is documented.
cspec gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: no VCEP Table 9 entry or validated benign protein assay was found for c.3941A>G; the reported paper labels its effect unknown.
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 PMID:16683254
BS4 Not assessed Not assessed: no non-segregating affected relatives or quantitative LR is available, and the ENIGMA BS4 supporting threshold is LR ≤0.48:1.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18 PMID:16683254
BP1 Met Met, strong: residue 1314 is outside ENIGMA critical domains and SpliceAI max delta is 0.001, below the <=0.1 threshold.
cspec spliceai
BP2 N/A Not applicable: the ENIGMA BRCA2 VCEP explicitly prohibits BP2 except as part of BS2 assessment.
cspec
BP3 N/A Not applicable: ENIGMA says do not use BP3, and c.3941A>G is a missense substitution rather than an in-frame insertion or deletion.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: Lys1314 lies outside ENIGMA's BRCA2 BP4 domains, aa 10-40 and aa 2481-3186, regardless of its benign-leaning predictor scores.
cspec spliceai bayesdel revel
BP5 Not assessed Not assessed: no exact-variant combined LR was available to evaluate the BP5 Supporting inequality LR <=0.48.
cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP6 N/A Not applicable: the VCEP says not to use BP6, and ClinVar has zero expert-panel submissions for this exact variant.
cspec clinvar
BP7 N/A Not applicable: c.3941A>G produces the missense change p.Lys1314Arg, whereas BP7 is limited to synonymous variants.
cspec
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