LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-14
Case ID: NM_000059.4_c.6698C_T_20261014_135100
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.6698C>T

BRCA2  · NP_000050.3:p.(Ala2233Val)  · NM_000059.4
GRCh37: chr13:32915190 C>T  ·  GRCh38: chr13:32341053 C>T
Gene: BRCA2 Transcript: NM_000059.4
Final call
VUS
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.(Ala2233Val)
gnomAD AF
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS: BP1 (Strong) is supported by residue 2233 being outside BRCA2 critical domains and SpliceAI maximum delta 0.014 indicating no predicted splicing impact.
Final determination: Under ENIGMA BRCA2 Version 1.2 Table 3, one Strong benign criterion without a second benign evidence type does not meet the Likely Benign combination, so the absence of qualifying pathogenic combinations yields VUS.
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.6698C>T is a missense substitution, whereas ENIGMA PVS1 covers null or canonical splice-site loss-of-function variants.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 spliceai
PS1 Not met Not met: no established pathogenic comparator producing p.Ala2233Val was identified, while the documented alternate p.Ala2233Asp is benign or uncertain.
cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS2 N/A Not applicable: ENIGMA BRCA2 v1.2 explicitly prohibits PS2 because de novo occurrence predictive capacity is uncalibrated.
cspec
PS3 Not assessed Not assessed: ENIGMA Table 9 contains no calibrated PS3 entry for c.6698C>T, p.Ala2233Val, or p.A2233V.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18
PS4 Not assessed Not assessed: no exact-variant case-control p-value, OR, or confidence interval was available to test p <=0.05, OR >=4, and lower confidence interval >2.0.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18 PMID:31911673
PM1 N/A Not applicable: ENIGMA BRCA2 explicitly prohibits PM1, and residue 2233 lies outside its listed amino-acid 10-40 and 2481-3186 domains.
cspec vcep_appendices_v1_2_2024_11_18
PM2 Not assessed Not assessed: the variant is absent from required non-cancer gnomAD subsets, but the ENIGMA PM2 rule requires regional read depth >=25 and no depth value is available.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no documented Fanconi-anemia phenotype or phased pathogenic BRCA2 variant in trans/cis is available for PM3 scoring.
cspec
PM4 N/A Not applicable: ENIGMA explicitly excludes PM4, and p.(Ala2233Val) changes one amino acid without altering protein length.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: ENIGMA repurposes PM5 for pathogenic PTC variants, whereas c.6698C>T produces the missense substitution p.Ala2233Val.
cspec vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable: ENIGMA BRCA2 v1.2 explicitly prohibits PM6 because de novo occurrence predictive capacity is uncalibrated.
cspec
PP1 Not assessed Not assessed: no affected-relative genotypes or co-segregation LR are available, so the PP1 threshold of LR >=2.08 cannot be evaluated.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PP2 N/A Not applicable: ENIGMA BRCA2 explicitly prohibits PP2 because benign missense variation is frequent in the gene.
cspec
PP3 Not met Not met: REVEL 0.555 is below the >=0.644 supporting PP3 threshold and remains in the non-informative gray zone.
cspec revel
PP4 Not assessed Not assessed: no exact-variant combined clinical LR was available to test PP4 thresholds of >=2.08, >=4.3, >=18.7, or >=350.
cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_pmid_17924331_easton_2007_ajhg
PP5 N/A Not applicable: ENIGMA says do not use PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification.
cspec clinvar
BA1 Not met Not met: the variant is absent from required non-cancer gnomAD subsets, far below the ENIGMA BA1 threshold of FAF >0.001.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS1 Not met Not met: the variant is absent from required non-cancer gnomAD subsets, below both ENIGMA BS1 thresholds of FAF >0.00002 and >0.0001.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: no qualifying patient-level homozygote or trans co-occurrence with age and Fanconi-anemia phenotype data is available for BS2 point scoring.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS3 Not assessed Not assessed: ENIGMA Table 9 contains no calibrated BS3 entry for c.6698C>T, p.Ala2233Val, or p.A2233V.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18
BS4 Not assessed Not assessed: no affected-relative non-segregation data or benign-direction LR are available, so the BS4 threshold of LR <=0.48 cannot be evaluated.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP1 Met Met, Strong: residue 2233 is outside BRCA2 critical domains and SpliceAI max delta 0.014 is below the <=0.1 no-splicing threshold.
cspec spliceai
BP2 N/A Not applicable: the ENIGMA BRCA2 VCEP specifies that BP2 must not be used and is restricted to BS2 context.
cspec
BP3 N/A Not applicable: ENIGMA explicitly excludes BP3, and this variant is a missense substitution rather than an in-frame repeat-region indel.
cspec vcep_specifications_v1_2_2024_11_18
BP4 Not met Not met: REVEL 0.555 exceeds the <=0.29 supporting BP4 threshold and is therefore a gray-zone missense result.
cspec revel
BP5 Not assessed Not assessed: no exact-variant combined LR was available to test BP5's benign-direction thresholds of <=0.48, <=0.23, <=0.05, or <=0.00285.
cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_pmid_17924331_easton_2007_ajhg
BP6 N/A Not applicable: ENIGMA says do not use BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification.
cspec clinvar
BP7 N/A Not applicable: p.Ala2233Val is a missense substitution, whereas BP7 is limited to synonymous or qualifying intronic variants.
cspec
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