LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-18
Case ID: NM_000059.4_c.1167G_A_20260918_143638
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.1167G>A

BRCA2  · NP_000050.3:p.(Pro389=)  · NM_000059.4
GRCh37: chr13:32906782 G>A  ·  GRCh38: chr13:32332645 G>A
Gene: BRCA2 Transcript: NM_000059.4
Final call
Likely Benign
BS1 supporting BP1 strong benign BP6 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.(Pro389=)
gnomAD AF
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BS1 Supporting: gnomAD v3.1 non-cancer genome FAF 6.803e-05 falls within ENIGMA's benign-supporting frequency interval.
2
BP1 Strong benign: synonymous residue 389 is outside the approved BRCA2 functional domains and SpliceAI max delta is 0.001.
3
BP6 Supporting benign: the exact variant has a three-star ENIGMA expert-panel Likely benign classification in ClinVar.
Final determination: Under ENIGMA BRCA2 Version 1.2's conflicting-evidence point system, BS1 Supporting (-1), BP1 Strong benign (-4), and BP6 Supporting benign (-1) total -6, corresponding 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: c.1167G>A is synonymous, p.Pro389=, and is outside ENIGMA's PVS1 null-variant categories.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS1 N/A Not applicable: the synonymous p.(P389=) variant has no established pathogenic same-missense or identical-splice-event comparator, and SpliceAI max delta is 0.001.
cspec vcep_specifications_v1_2_2024_11_18 spliceai
PS2 N/A Not applicable: ENIGMA explicitly prohibits PS2 for BRCA1/2 because de novo predictive capacity is uncalibrated.
cspec
PS3 Not assessed Not assessed: no calibrated damaging functional assay was reported for c.1167G>A (p.Pro389=), and SpliceAI max delta 0.001 is not PS3 evidence.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:17100994 spliceai
PS4 Not assessed Not assessed: 6/793 cases versus 0/167 controls was reported, but the required PS4 p-value, OR >=4, and lower confidence limit excluding 2.0 are unavailable.
cspec PMID:17100994 vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM1 N/A Not applicable: ENIGMA marks PM1 do not use, and residue 389 lies outside the approved BRCA2 domains at aa 10-40 and 2481-3186.
cspec vcep_appendices_v1_2_2024_11_18
PM2 Not met Not met: the variant is present in gnomAD v2.1 non-cancer exomes at AF 3.81942e-05 and gnomAD v3.1 non-cancer genomes at AF 6.75941e-05.
cspec gnomad_v2
PM3 Not assessed Not assessed: no documented Fanconi anemia phenotype, same-gene pathogenic variant, or phase information is available to satisfy the ENIGMA PM3 rule.
cspec PMID:17100994
PM4 N/A Not applicable: p.Pro389= changes protein sequence length by 0 amino acids, and ENIGMA explicitly excludes PM4.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: ENIGMA repurposes PM5 exclusively for genomic PTC variants, whereas this variant is synonymous and not a protein-termination codon.
cspec vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable: ENIGMA explicitly prohibits PM6 for BRCA1/2 because de novo predictive capacity is uncalibrated.
cspec
PP1 Not assessed Not assessed: no quantitative co-segregation LR or affected-relative meioses are available to reach the ENIGMA PP1 threshold of LR >=2.08.
cspec PMID:17100994 PMID:16949048
PP2 N/A Not applicable: ENIGMA marks PP2 do not use for BRCA2, and the queried variant is synonymous rather than missense.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Not met Not met: SpliceAI maximum delta 0.001 is below the ENIGMA PP3 threshold of 0.2 for silent variants.
cspec spliceai vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP4 Not assessed Not assessed: no exact BRCA2 c.1167G>A combined clinical-history LR was found for comparison with the PP4 threshold >=2.08.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331
PP5 Not met Not met: the exact-variant ClinVar expert panel classified c.1167G>A as Likely benign, not Pathogenic or Likely pathogenic.
cspec clinvar
BA1 Not met Not met: maximum applicable non-cancer FAF is 6.803e-05, below the ENIGMA BA1 threshold of >0.001.
cspec gnomad_v2
BS1 Met Met at Supporting: gnomAD v3.1 non-cancer genome grpmax FAF 6.803e-05 falls between the ENIGMA BS1 Supporting limits >2e-05 and <=1e-04.
cspec gnomad_v2
BS2 Not assessed Not assessed: gnomAD records show 0 homozygotes, but ENIGMA excludes frequency-dataset homozygotes and provides no qualifying phenotyped individual-level BS2 points.
cspec gnomad_v2
BS3 Not assessed Not assessed: no calibrated benign functional assay was reported for c.1167G>A (p.Pro389=), and SpliceAI max delta 0.001 is not BS3 evidence.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:17100994 spliceai
BS4 Not assessed Not assessed: no quantitative non-segregation LR or affected-relative genotype data are available to reach the ENIGMA BS4 threshold of LR <=0.48.
cspec PMID:17100994 PMID:16949048 vcep_supplementarytables_v1_2_2024_11_18
BP1 Met Met, Strong: synonymous residue 389 is outside BRCA2 domains aa 10-40 and 2481-3186, with SpliceAI max delta 0.001 versus the ≤0.1 threshold.
cspec vcep_appendices_v1_2_2024_11_18 spliceai
BP2 N/A Not applicable: ENIGMA BRCA2 specification states BP2 is not used and is applied only in the context of BS2.
cspec
BP3 N/A Not applicable: c.1167G>A is a synonymous substitution, not an in-frame insertion/deletion in a repetitive region.
cspec vcep_specifications_v1_2_2024_11_18
BP4 Not met Not met: SpliceAI maximum delta 0.001 is below 0.1, but ENIGMA BP4 requires a silent variant inside a clinically important BRCA2 domain.
cspec spliceai vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP5 Not assessed Not assessed: no exact BRCA2 c.1167G>A clinical-history LR was available for the BP5 comparison LR <=0.48.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331
BP6 Met Met, Supporting: the exact variant has a ClinVar 3-star ENIGMA expert-panel classification of Likely benign.
clinvar
BP7 Not met Not met: Pro389 lies outside ENIGMA's qualifying domains, and no mRNA-only assay supports the alternative BP7_Strong route.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
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