LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-10
Case ID: NM_000059.4_c.4183G_T_20260810_210523
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.4183G>T

BRCA2  · NP_000050.3:p.(Ala1395Ser)  · NM_000059.4
GRCh37: chr13:32912675 G>T  ·  GRCh38: chr13:32338538 G>T
Gene: BRCA2 Transcript: NM_000059.4
Final call
Likely Benign
PP4 supporting 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.(Ala1395Ser)
gnomAD AF
1.2474676406894006e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PP4 (Supporting): ENIGMA combined multifactorial likelihood LR 2.225 for this exact variant meets the >=2.08 supporting threshold.
2
BP1 (Strong): missense p.Ala1395Ser lies outside BRCA2's clinically important functional domains with no predicted splicing impact (SpliceAI max delta 0.00).
3
Overall Likely Benign: conflicting-evidence point scoring (PP4 +1, BP1 -4, net -3) places the variant in the -6 to -2 Likely Benign range.
Final determination: ENIGMA BRCA1/BRCA2 VCEP v1.2 Table 3 conflicting-evidence point system: PP4 Supporting (+1) and BP1_Strong (-4) net to -3, within the Likely Benign range (-6 to -2), because no standalone Table 3 combination rule (pathogenic or benign) is fully satisfied.
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: missense substitution, not a loss-of-function variant class, with no predicted splicing impact (SpliceAI max delta 0.00).
cspec spliceai clinvar
PS1 Not met Not met: no pathogenic or likely pathogenic variant producing the same p.Ala1395Ser change exists (0 comparator candidates).
cspec clinvar spliceai pm5_candidates
PS2 Not assessed Not assessed: no parental testing or documentation of de novo occurrence was available.
PMID:25741868
PS3 Not met Not met: no well-established functional studies supporting a damaging effect exist for this variant.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:31131967 PMID:31911673 oncokb clinvar spliceai
PS4 Not assessed Not assessed: no case-control or prevalence data for this exact variant was available.
cspec clinvar PMID:31131967 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PM1 N/A Not applicable: the ENIGMA VCEP does not use PM1 for BRCA2, capturing domain analysis through PP3/BP4 instead.
cspec
PM2 Not met Not met: present in gnomAD v4.1 (AF 1.7e-06), so the strict absence requirement of PM2 is not demonstrated.
gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3 N/A Not applicable: no Fanconi anemia phenotype or second co-occurring BRCA2 variant is documented.
cspec clinvar
PM4 N/A Not applicable: single-nucleotide missense with no protein length change, and ENIGMA excludes PM4 for BRCA1/BRCA2.
cspec
PM5 N/A Not applicable: ENIGMA applies PM5 only to protein-termination-codon variants, not missense changes.
cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6 Not assessed Not assessed: no evidence that the variant arose de novo.
PMID:25741868
PP1 Not assessed Not assessed: no family segregation data or quantitative co-segregation likelihood ratio was available.
cspec vcep_specifications_v1_2_2024_11_18 PMID:31131967 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PP2 N/A Not applicable: the ENIGMA VCEP does not use PP2 for BRCA2.
cspec
PP3 Not met Not met: BayesDel no-AF -0.32 falls below the 0.30 threshold and SpliceAI max delta 0.00 below 0.2.
cspec spliceai bayesdel revel
PP4 Met Met (Supporting): ENIGMA combined multifactorial likelihood LR 2.225 for this exact variant meets the >=2.08 threshold.
cspec PMID:31131967 vcep_humu_40_1557_s001 PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr
PP5 N/A Not applicable: ENIGMA VCEP does not use PP5, and no expert-panel pathogenic classification exists.
cspec clinvar
BA1 Not met Not met: gnomAD FAF 2.8e-07 is far below the >0.1% BA1 threshold.
gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1 Not met Not met: gnomAD FAF 2.8e-07 is below even the 0.002% BS1-Supporting threshold.
gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2 Not assessed Not assessed: no proband phenotype data to score the ENIGMA BS2 points table.
cspec
BS3 Not met Not met: no well-established functional assay demonstrates no damaging effect on protein function.
cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:31131967 PMID:31911673 oncokb clinvar spliceai
BS4 Not assessed Not assessed: no co-segregation or non-segregation likelihood ratio data was available.
cspec vcep_specifications_v1_2_2024_11_18 PMID:31131967 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP1 Met Met (Strong): missense p.Ala1395Ser lies outside BRCA2's functional domains with SpliceAI max delta 0.00.
cspec spliceai PMID:31911673
BP2 N/A Not applicable: the ENIGMA VCEP does not apply BP2 to BRCA2.
cspec clinvar
BP3 N/A Not applicable: the ENIGMA VCEP does not apply BP3; this is a missense, not an in-frame indel.
cspec
BP4 Not met Not met: p.Ala1395Ser lies outside the BRCA2 functional domains, failing BP4's domain-location requirement.
cspec spliceai bayesdel vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP5 Not met Not met: combined LR 2.225 is in the pathogenic direction, above the <=0.48 BP5 threshold.
cspec PMID:31131967 vcep_humu_40_1557_s001 PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr
BP6 N/A Not applicable: ENIGMA VCEP does not use BP6, and no expert-panel benign classification exists.
cspec clinvar
BP7 N/A Not applicable: BP7 applies to silent or intronic variants, not this missense substitution.
cspec clinvar vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
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