LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-07
Case ID: NM_000059.4_c.8039A_G_20260807_130851
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.8039A>G

BRCA2  · NP_000050.3:p.(Asp2680Gly)  · NM_000059.4
GRCh37: chr13:32937378 A>G  ·  GRCh38: chr13:32363241 A>G
Gene: BRCA2 Transcript: NM_000059.4
Final call
Likely Benign
PM2 supporting BS3 strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Asp2680Gly)
gnomAD AF
8.673617951910984e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Likely Neutral
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_000059.4:c.8039A>G (p.Asp2680Gly) is a missense variant in exon 18 of BRCA2, located within the DNA binding domain (aa 2481-3186).
2
The ENIGMA BRCA2 VCEP Table 9 assigns BS3 (Strong) to this variant based on calibrated functional assay data from Richardson et al. 2021 (PMID:33609447), which demonstrates that p.Asp2680Gly exhibits homologous recombination activity similar to benign control variants.
3
The variant is absent from gnomAD v2.1 and ultra-rare in gnomAD v4.1 (AF 8.67e-06, grpmax FAF 5.42e-06), satisfying PM2_Supporting per ENIGMA VCEP criteria.
4
In silico predictors do not meet ENIGMA VCEP thresholds for PP3 (BayesDel 0.285 < 0.30) or BP4 (BayesDel 0.285 > 0.18). SpliceAI predicts no splicing impact (delta 0.01).
5
No case-control, segregation, or clinical-history LR data are available to support PS4, PP1, PP4, BS4, or BP5.
6
Applying the ENIGMA point system: BS3_Strong (-4) + PM2_Supporting (+1) = -3 points, which falls in the Likely Benign range (-6 to -2).
Final determination: Per ENIGMA BRCA2 VCEP v1.2 conflicting evidence rule, when both pathogenic and benign criteria are met, the point-based scoring system is used: BS3_Strong (-4 points) + PM2_Supporting (+1 point) = -3 points, which falls in the Likely Benign range (-6 to -2).
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 NM_000059.4:c.8039A>G is a missense substitution (p.Asp2680Gly), not a null variant (nonsense, frameshift, or canonical splice site). PVS1 is applicable only to null variants per the ENIGMA BRCA2 VCEP v1.2 framework.
PS1 Not met No previously classified pathogenic missense variant at the same amino acid residue (Asp2680) was identified. No comparator variant satisfying the ENIGMA BRCA2 PS1 rule (same residue, pathogenic classification, SpliceAI ≤0.1) is available.
clinvar spliceai
PS2 N/A Marked Not Applicable by the ENIGMA BRCA2 VCEP v1.2 specification.
cspec
PS3 Not met The ENIGMA BRCA2 VCEP Table 9 assigns BS3 (Strong) to this variant based on calibrated functional data from Richardson 2021 (PMID:33609447), reporting protein function similar to benign control variants. No evidence of a damaging functional effect; PS3 is not met.
vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447
PS4 Not met No case-control data demonstrating significantly increased prevalence of NM_000059.4:c.8039A>G in affected individuals compared to controls is available. The variant is ultra-rare (gnomAD v4.1 AF 8.67e-06).
gnomad_v4
PS5 N/A PS5 is not a standalone criterion in the ENIGMA BRCA2 VCEP v1.2 framework.
cspec
PM1 N/A Marked Not Applicable by the ENIGMA BRCA2 VCEP v1.2 specification.
cspec
PM2 Met NM_000059.4:c.8039A>G is absent from gnomAD v2.1 (non-cancer, exome only subset), satisfying the ENIGMA BRCA2 VCEP PM2_Supporting rule for absence from an outbred population control dataset.
gnomad_v2 gnomad_v4 cspec
PM5 N/A The ENIGMA BRCA2 VCEP repurposes PM5 for PTC (protein termination codon) variants only. NM_000059.4:c.8039A>G is a missense substitution, not a truncating variant.
pm5_candidates cspec
PM6 N/A Marked Not Applicable by the ENIGMA BRCA2 VCEP v1.2 specification.
cspec
PP1 Not met No co-segregation data is available for NM_000059.4:c.8039A>G. No quantitative co-segregation analysis (LR ≥2.08 required for PP1_Supporting) has been performed.
PP2 N/A Marked Not Applicable by the ENIGMA BRCA2 VCEP v1.2 specification.
cspec
PP3 Not met Although p.Asp2680Gly is located within the BRCA2 DNA binding domain (aa 2481-3186), the ENIGMA VCEP PP3 rule requires BayesDel no-AF score ≥0.30. The observed BayesDel score is 0.285, falling below the threshold. SpliceAI delta is 0.01 (≤0.20). No in silico prediction meets the VCEP PP3 thresholds.
bayesdel spliceai revel vcep_supplementarytables_v1_2_2024_11_18
PP4 Not met The variant is absent from the Li et al. 2020 (PMID:31853058) clinical-history LR table. The combined multifactorial LR from Parsons et al. 2019 (SuppT1 of HUMU-40-1557-s001) is 0.84, which falls in the neutral zone (>0.48 and <2.08). Neither PP4 nor BP5 thresholds are met.
vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 PMID:31853058
PP5 N/A Marked Not Applicable by the ENIGMA BRCA2 VCEP v1.2 specification. ClinVar review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold for the PP5 override rule.
cspec clinvar
BA1 Not met The ENIGMA BRCA2 VCEP BA1 rule requires filter allele frequency >0.1% (FAF >0.001). The observed grpmax FAF in gnomAD v4.1 is 5.42e-06 (0.000542%), far below the BA1 threshold. The variant is absent from gnomAD v2.1.
gnomad_v2 gnomad_v4 cspec
BS1 Not met The ENIGMA BRCA2 VCEP BS1_Supporting threshold requires FAF >0.002% (FAF >0.00002). The observed grpmax FAF in gnomAD v4.1 is 5.42e-06 (0.000542%), which is below the BS1_Supporting threshold of 0.002%.
gnomad_v2 gnomad_v4 cspec
BS2 Not met BS2 requires proband-level data to assess absence of Fanconi Anemia features, scored per the ENIGMA Specifications Table 8 point system. No proband clinical data are available for this assessment.
BS3 Met The ENIGMA BRCA2 VCEP Table 9 assigns BS3 (Strong) to NM_000059.4:c.8039A>G (p.Asp2680Gly). One calibrated study (Richardson 2021, PMID:33609447) reports that this variant exhibits protein function similar to benign control variants in a validated functional assay of BRCA2 homologous recombination activity.
vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447 vcep_supplementarytables_v1_2_2024_11_18
BS4 Not met No lack-of-segregation data are available for NM_000059.4:c.8039A>G. BS4 requires quantitative co-segregation analysis showing LR ≤0.48 (Supporting).
BP1 N/A BP1 applies to missense variants outside a clinically important functional domain. p.Asp2680Gly is located within the BRCA2 DNA binding domain (aa 2481-3186), a (potentially) clinically important functional domain per ENIGMA VCEP v1.2 Appendix J.
cspec
BP2 N/A Marked Not Applicable by the ENIGMA BRCA2 VCEP v1.2 specification.
cspec
BP4 Not met The ENIGMA BRCA2 VCEP BP4 rule for missense variants inside a clinically important functional domain requires BayesDel no-AF ≤0.18 AND SpliceAI ≤0.1. While SpliceAI delta is 0.01 (≤0.1), the BayesDel no-AF score is 0.285, exceeding the 0.18 threshold.
bayesdel spliceai cspec
BP5 Not met The variant is absent from the Li et al. 2020 (PMID:31853058) clinical-history LR table. The combined multifactorial LR from Parsons et al. 2019 is 0.84, which falls in the neutral zone (>0.48 and <2.08). BP5_Supporting requires LR ≤0.48.
vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001
BP6 N/A Marked Not Applicable by the ENIGMA BRCA2 VCEP v1.2 specification. ClinVar review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold for the BP6 override rule.
cspec clinvar
BP7 Not met BP7 applies to mRNA assay data showing no damaging effect. The ENIGMA VCEP Table 9 assigned BS3 (protein-level functional data) rather than BP7 (mRNA-level). No mRNA-specific assay demonstrating no splicing impact has been identified for this variant beyond the SpliceAI prediction (delta 0.01, no splicing predicted). BP7 requires experimental mRNA evidence per Figure 1B of the specification.
spliceai cspec
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