LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-06
Case ID: NM_000059.4_c.6444T_C_20261006_141237
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.6444T>C

BRCA2  · NP_000050.3:p.(Ser2148=)  · NM_000059.4
GRCh37: chr13:32914936 T>C  ·  GRCh38: chr13:32340799 T>C
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.(Ser2148=)
gnomAD AF
1.884126236457843e-05 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BS1 supporting reflects the maximum non-cancer gnomAD FAF of 0.00007569.
2
Likely Benign: BP1 strong applies to the synonymous change outside approved BRCA2 domains with SpliceAI max delta 0.01.
3
Likely Benign: BP6 supporting is supported by the exact ClinVar expert-panel Likely benign classification.
Final determination: Under ENIGMA BRCA2 VCEP Version 1.2 Table 3, conflicting evidence is scored by points: BS1 Supporting +1, BP1 Strong benign -4, and BP6 Supporting benign -1 total -4, which falls in the Likely Benign range of -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 Not applicable: c.6444T>C is synonymous, not a VCEP-defined null variant, and SpliceAI max delta is 0.01.
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 variant is synonymous, and SpliceAI maximum delta 0.01 shows no qualifying splice event for PS1.
cspec spliceai vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS2 N/A Not applicable: ENIGMA explicitly prohibits PS2 because de novo occurrences lack calibrated predictive value for BRCA2-related cancers.
cspec
PS3 Not assessed Not assessed: no variant-specific damaging functional assay or governing ENIGMA Table 9 entry was found for c.6444T>C (p.Ser2148=).
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
PS4 Not assessed Not assessed: no exact-variant case-control p-value, OR, and confidence interval were available to compare with the ENIGMA PS4 thresholds.
cspec 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 excludes PM1, and residue Ser2148 lies outside the approved domains aa 10-40 and aa 2481-3186.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not met Not met: the variant is present at 6/215906 alleles in non-cancer gnomAD v2.1 exomes, so ENIGMA's required absence from both datasets is not satisfied.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2
PM3 Not assessed Not assessed: no documented Fanconi anemia phenotype, chromosome-breakage result, or phased pathogenic/likely pathogenic BRCA2 variant supports the VCEP PM3 requirement.
cspec
PM4 N/A Not applicable: the variant is synonymous, p.(Ser2148=), with no protein-length change, and ENIGMA marks PM4 not applicable.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: this is a synonymous variant, whereas ENIGMA PM5 is excluded for missense changes and reserved for PVS1 protein-termination variants.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable: ENIGMA explicitly prohibits PM6 because uncalibrated de novo occurrences do not provide usable BRCA2 evidence.
cspec
PP1 Not assessed Not assessed: no family-level segregation data or quantitative LR was available, so ENIGMA PP1 thresholds of 2.08, 4.3, 18.7, and 350 cannot be applied.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PP2 N/A Not applicable: ENIGMA excludes PP2 for BRCA2, and this variant is synonymous rather than missense.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP3 Not met Not met: SpliceAI max delta 0.01 is below the ENIGMA PP3 threshold of 0.2 for predicted splicing in silent variants.
vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
PP4 Not assessed Not assessed: no exact-variant multifactorial likelihood ratio was available to compare with the ENIGMA PP4 threshold of >=2.08.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331
PP5 Not met Not met: the exact ClinVar expert-panel classification is Likely benign, whereas PP5 requires Pathogenic or Likely pathogenic expert-panel classification.
clinvar cspec
BA1 Not met Not met: maximum non-cancer gnomAD FAF is 0.00007569, below the ENIGMA BA1 threshold of greater than 0.001.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2
BS1 Met Met at supporting: maximum non-cancer gnomAD FAF 0.00007569 falls between the ENIGMA BS1 Supporting limits of greater than 0.00002 and at most 0.0001.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2
BS2 Not assessed Not assessed: gnomAD reports zero homozygotes, but ENIGMA requires phenotyped clinical or research cohort observations rather than population-frequency homozygotes for BS2.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: no variant-specific benign functional assay or governing ENIGMA Table 9 entry was found for c.6444T>C (p.Ser2148=).
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
BS4 Not assessed Not assessed: no affected-relative non-segregation data or quantitative LR was available, so ENIGMA BS4 thresholds of 0.48, 0.23, 0.05, and 0.00285 cannot be applied.
cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP1 Met Met at strong: synonymous residue Ser2148 is outside approved domains, and SpliceAI maximum delta 0.01 meets the <=0.1 threshold.
cspec spliceai vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP2 N/A Not applicable: the ENIGMA BRCA2 VCEP explicitly prohibits BP2 and permits it only in the context of BS2.
cspec
BP3 N/A Not applicable: BP3 is VCEP-excluded, and c.6444T>C is a synonymous substitution rather than an in-frame insertion/deletion.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: Ser2148 lies outside ENIGMA BRCA2 functional domains eligible for silent-variant BP4, despite SpliceAI max delta 0.01.
vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BP5 Not assessed Not assessed: no exact-variant multifactorial LR was available for comparison with the BP5 Supporting threshold of <=0.48.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 PMID:17924331
BP6 Met Met, Supporting: ClinVar expert panel classifies the exact variant as Likely benign, satisfying the requested BP6 expert-panel rule.
clinvar cspec
BP7 N/A Not applicable: BP7 requires a silent variant inside an ENIGMA BRCA2 functional domain with BP4 met, but Ser2148 is outside both domains.
vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
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