LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-01
Case ID: NM_000059.4_c.8432A_G_20261001_121615
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.8432A>G

BRCA2  · NP_000050.3:p.(Asp2811Gly)  · NM_000059.4
GRCh37: chr13:32944639 A>G  ·  GRCh38: chr13:32370502 A>G
Gene: BRCA2 Transcript: NM_000059.4
Final call
Likely Benign
BS1 supporting (benign) 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.(Asp2811Gly)
gnomAD AF
9.914057513926153e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BS1 (supporting benign) is met on a maximum non-founder filter allele frequency of 5.65e-05 in gnomAD v2.1 non-cancer exomes.
2
Likely Benign: BP5 (supporting benign) is met on an ENIGMA combined clinical likelihood ratio of 0.430.
Final determination: Under ENIGMA BRCA2 VCEP Version 1.2 Table 3, two Supporting (Benign) criteria (BS1 plus BP5) combine to 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: p.Asp2811Gly is a missense substitution, and ENIGMA PVS1 applies only to null variants; SpliceAI max delta 0.03 excludes a splice-null.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_pmid_22505045_houdayer_2012_hummutat spliceai pvs1_variant_assessment pvs1_gene_context
PS1 Not met Not met: c.8432A>G p.Asp2811Gly is itself classified (Likely) Benign by ENIGMA (posterior 0.0131) and no pathogenic variant carries the same amino-acid change.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 clinvar PMID:10717622
PS2 N/A Not applicable: the ENIGMA BRCA2 VCEP explicitly prohibits PS2 because de novo occurrence predictive capacity is uncalibrated.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
PS3 Not met Not met: ENIGMA Table 9, the governing functional-assay table, has no entry for c.8432A>G (p.Asp2811Gly), and no published assay reports a damaging effect.
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 vcep_supplementarytables_v1_2_2024_11_18 PMID:10717622 PMID:31131967 PMID:31112341 PMID:25741868
PS4 Not met Not met: no variant-level case-control odds ratio exists for c.8432A>G to satisfy the ENIGMA PS4 requirement of OR >= 4 (p <= 0.05).
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001 gnomad_v2 PMID:10717622 PMID:12692171 PMID:17392385
PM1 N/A Not applicable: the ENIGMA BRCA2 v1.2 specification retires PM1 ('Do not use; considered as component of PP3/BP4'), though Asp2811 does lie in the BRCA2 DNA-binding domain (aa 2481-3186).
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM2 Not met Not met: the variant is present in controls (2/236,848 alleles, AF 8.44e-06 in gnomAD v2.1 non-cancer exomes), so the 'absent from controls' requirement fails.
cspec gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM3 Not met Not met: no Fanconi anemia proband and no BRCA2 P/LP variant in trans or homozygous, so the VCEP PM3 points scheme cannot be triggered.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_pmid_31853058_brca2_clinical_history_lr clinvar PMID:31131967
PM4 N/A Not applicable: p.Asp2811Gly changes one residue without altering protein length, and ENIGMA v1.2 lists PM4 as do-not-use.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM5 N/A Not applicable: ENIGMA v1.2 retires classic missense PM5 and repurposes it to PM5_PTC for truncating variants only, and c.8432A>G is a missense change.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 pm5_candidates
PM6 N/A Not applicable: the ENIGMA BRCA2 VCEP explicitly prohibits PM6 because de novo occurrence predictive capacity is uncalibrated.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
PP1 Not assessed Not assessed: the ENIGMA tables carry no co-segregation LR for c.8432A>G, so the PP1 threshold of LR >=2.08 cannot be reached.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18 clinvar
PP2 N/A Not applicable: ENIGMA BRCA2 v1.2 retires PP2 ('Do not use - high frequency of benign missense variants'), so a BRCA2 missense variant cannot receive it.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Not met Not met: in-domain missense BayesDel no-AF 0.191743 is below the BRCA2 PP3 cutoff of 0.30 and SpliceAI 0.032 is below the 0.2 splice threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 bayesdel spliceai revel vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PP4 Not met Not met: the ENIGMA combined clinical LR for this variant is 0.430, far below the 2.08 PP4 threshold and directed against pathogenicity.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18 vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331 PMID:31131967
PP5 Not met Not met: ClinVar VCV000052585 has no expert-panel assertion (11 single-submitter laboratory submissions, 1-star, conflicting), so the PP5 requirement for an expert-panel pathogenic call is unmet.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
BA1 Not met Not met: maximum non-founder FAF 5.65e-05 (East Asian, gnomAD v2.1 non-cancer exomes) vs the >0.001 BA1 stand-alone threshold.
cspec gnomad_v2 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS1 Met Met at supporting strength: maximum non-founder FAF 5.65e-05 (East Asian) falls in the >0.00002 to <=0.0001 BS1_Supporting band but below the 0.0001 strong threshold.
cspec gnomad_v2 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS2 Not met Not met: BS2 requires proband-level co-occurrent/homozygote points (Table 8) and none are present, with 0 gnomAD homozygotes observed.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS3 Not met Not met: no calibrated functional assay reports wild-type-like function for this variant, and the governing ENIGMA Table 9 has no entry for c.8432A>G.
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 vcep_supplementarytables_v1_2_2024_11_18 PMID:10717622 PMID:31131967 PMID:31112341 PMID:25741868
BS4 Not assessed Not assessed: no co-segregation LR exists for c.8432A>G, so the BS4 threshold of LR <=0.48 is not evaluable.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18 clinvar
BP1 Not met Not met: BP1_Strong requires a missense variant outside a clinically important domain, but Asp2811 lies within the BRCA2 DNA-binding domain (aa 2481-3186).
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: ENIGMA BRCA2 v1.2 marks BP2 'Do not use - applied only in the context of BS2', and no cis/trans pathogenic variant is documented.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
BP3 N/A Not applicable: p.Asp2811Gly is a missense substitution, not an in-frame indel in a functionless repeat region, and ENIGMA v1.2 lists BP3 as do-not-use.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP4 Not met Not met: BayesDel no-AF 0.191743 exceeds the BRCA2 BP4 cutoff of 0.18, so the required protein-impact component fails despite SpliceAI 0.032 <= 0.1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 bayesdel spliceai revel vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP5 Met Met at Supporting: the ENIGMA combined clinical LR for this variant is 0.430, which satisfies the BP5 threshold of <=0.48 and >0.23.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18 vcep_pmid_31853058_brca2_clinical_history_lr PMID:31131967 PMID:31853058 PMID:17924331
BP6 Not met Not met: the ClinVar Likely benign calls for this variant come only from single-submitter laboratories (VCV000052585, no expert panel), which cannot trigger BP6.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
BP7 N/A Not applicable: BP7 applies only to synonymous variants with no predicted splice impact, and c.8432A>G is a missense (p.Asp2811Gly) substitution.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
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