LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-04
Case ID: NM_000059.4_c.8167G_C_20261104_151745
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.8167G>C

BRCA2  · NP_000050.3:p.(Asp2723His)  · NM_000059.4
GRCh37: chr13:32937506 G>C  ·  GRCh38: chr13:32363369 G>C
Gene: BRCA2 Transcript: NM_000059.4
Final call
Pathogenic
PS3 strong PP1 very strong PP3 supporting PP4 strong PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Asp2723His)
gnomAD AF
1.3010781601020045e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS3 Strong reflects three calibrated functional studies showing protein function similar to pathogenic controls.
2
Pathogenic: PP1 Very Strong reflects complete co-segregation across 10 pedigrees with odds of 13,731:1.
3
Pathogenic: PP3 Supporting reflects a BayesDel no-AF score of 0.579612 above the 0.30 threshold.
4
Pathogenic: PP4 Strong reflects a multifactorial clinical-history likelihood ratio of 79.2565.
5
Pathogenic: PP5 Supporting reflects a three-star ENIGMA expert-panel ClinVar Pathogenic assertion.
Final determination: Under the ENIGMA BRCA2 Version 1.2 Table 3 rules, one Very Strong pathogenic criterion plus at least one Strong pathogenic criterion yields Pathogenic; PP1 Very Strong and PS3 Strong satisfy 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.8167G>C causes p.Asp2723His, a missense substitution, whereas ENIGMA PVS1 applies to null variants such as nonsense, frameshift, deletion, duplication, or canonical splice-site variants.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS1 Not met Not met: the only VCEP-listed likely pathogenic alternate, p.Asp2723Gly, has documented exon 18 splicing and cannot serve as a protein-change PS1 reference.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:15290653 PMID:18451181
PS2 N/A Not applicable: the ENIGMA BRCA2 VCEP prohibits PS2 because de novo occurrences lack calibrated predictive capacity for relatively common BRCA1/2-related cancers.
cspec vcep_specifications_v1_2_2024_11_18
PS3 Met Met at Strong: ENIGMA Table 9 pre-assigns PS3 Strong from three calibrated studies showing protein function similar to pathogenic controls.
vcep_specifications_table9_v1_2_2024_11_18 PMID:15290653 PMID:18451181
PS4 Not met Not met: no verified variant-specific case-control p-value, OR >=4, or confidence interval excluding 2.0 was available.
cspec vcep_supplementarytables_v1_2_2024_11_18 PMID:15290653 PMID:18451181
PM1 N/A Not applicable: residue 2723 is in the DNA-binding domain, but ENIGMA explicitly directs that PM1 is not used and domain evidence belongs under PP3/BP4.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not met Not met: the variant occurs once in gnomAD v3.1 non-cancer, so it is not absent from the VCEP-required control datasets.
cspec gnomad_v2 gnomad_v4 vcep_supplementarytables_v1_2_2024_11_18
PM3 Not met Not met: D2723H was never observed with a proven deleterious mutation, and no qualifying Fanconi Anemia phenotype or chromosome-breakage result is reported.
cspec vcep_specifications_v1_2_2024_11_18 PMID:15290653
PM4 N/A Not applicable: p.Asp2723His is a missense substitution, not an in-frame deletion, in-frame insertion, or stop-loss protein-length change, and ENIGMA marks PM4 'Do not use.'
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: c.8167G>C is missense, while ENIGMA reserves PM5 for exon-specific protein-termination-codon variants.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM6 N/A Not applicable: the ENIGMA BRCA2 VCEP prohibits PM6 because de novo occurrences lack calibrated predictive capacity for relatively common BRCA1/2-related cancers.
cspec vcep_specifications_v1_2_2024_11_18
PP1 Met Met, Very Strong: complete co-segregation in 10 pedigrees produced odds of 13,731:1, exceeding the VCEP PP1 Very Strong threshold of 350:1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:15290653
PP2 N/A Not applicable: ENIGMA says not to use PP2 for BRCA2 because the gene has a high frequency of benign missense variants.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Met Met: BayesDel no-AF is 0.579612, exceeding the ENIGMA BRCA2 PP3 protein-impact threshold of 0.30 for missense variants in the DNA-binding domain.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 bayesdel spliceai
PP4 Met Met, Strong: clinical-history LR 79.2565 >= 18.7, meeting ENIGMA's PP4 Strong threshold.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5 Met Met, Supporting: ClinVar records an ENIGMA expert-panel Pathogenic assertion with three review stars.
cspec clinvar
BA1 Not met Not met: gnomAD v3.1 non-cancer grpmax FAF is 0, below the VCEP BA1 threshold of >0.001.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: gnomAD v3.1 non-cancer grpmax FAF is 0, below the BS1 Supporting threshold of >0.00002.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: gnomAD reports 0 homozygotes, but no qualifying phenotyped healthy-adult cohort observations or BS2 points are available.
cspec gnomad_v2 gnomad_v4 vcep_appendices_v1_2_2024_11_18
BS3 Not met Not met: ENIGMA Table 9 assigns PS3 Strong because three calibrated studies show damaging function, not the no-damage result required for BS3.
vcep_specifications_table9_v1_2_2024_11_18 PMID:15290653 PMID:18451181
BS4 Not assessed Not assessed: no quantitative benign-direction LR or affected-relative non-segregation evidence is available, while the reported LR supports complete co-segregation.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:15290653
BP1 N/A Not applicable: residue 2723 is inside the ENIGMA DNA-binding domain, although SpliceAI max delta is 0.011 and below 0.1.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: the ENIGMA VCEP says BP2 is not applicable and may be applied only in the context of BS2.
cspec vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: c.8167G>C is a missense substitution, not an in-frame deletion or insertion in a repetitive region, and ENIGMA marks BP3 'Do not use.'
cspec vcep_specifications_v1_2_2024_11_18
BP4 Not met Not met: SpliceAI maximum delta is 0.011, but BayesDel no-AF is 0.579612, above the ENIGMA BRCA2 BP4 no-impact cutoff of 0.18.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 bayesdel spliceai
BP5 Not met Not met: clinical-history LR 79.2565 <= 0.48? no, so it does not meet ENIGMA's BP5 Supporting threshold.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6 Not met Not met: ClinVar's three-star ENIGMA expert-panel assertion is Pathogenic, not benign.
cspec clinvar
BP7 N/A Not applicable: BP7 covers missense variants outside the ENIGMA functional domain, whereas p.Asp2723His lies inside the BRCA2 DNA-binding domain.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
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