LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-29
Case ID: NM_000059.4_c.8524C_T_20261029_124230
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.8524C>T

BRCA2  · NP_000050.3:p.(Arg2842Cys)  · NM_000059.4
GRCh37: chr13:32945129 C>T  ·  GRCh38: chr13:32370992 C>T
Gene: BRCA2 Transcript: NM_000059.4
Final call
VUS
PP3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Arg2842Cys)
gnomAD AF
3.9658884023790374e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PP3 Supporting: BayesDel no-AF 0.371621 exceeds the ENIGMA protein-impact threshold of 0.30.
2
VUS: PP3 Supporting alone does not meet an ENIGMA BRCA2 V1.2 pathogenic or benign combination rule.
Final determination: Under ENIGMA BRCA2 V1.2 Table 3, a single pathogenic Supporting criterion does not satisfy any classification combination; therefore the final call is 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.8524C>T produces missense p.Arg2842Cys, whereas ENIGMA PVS1 applies to specified null variants such as nonsense, frameshift, splice-site, initiation-codon, or exon-deletion variants.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18
PS1 Not met Not met: no VCEP-established pathogenic or likely pathogenic alternate change at Arg2842 is available, although c.8524C>T itself shows no routine splicing aberration.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 PMID:23108138 PMID:24123850
PS2 N/A Not applicable: the ENIGMA VCEP explicitly prohibits PS2 because BRCA1/2-related cancers are relatively common and de novo predictive capacity is uncalibrated.
cspec vcep_specifications_v1_2_2024_11_18
PS3 Not met Not met: ENIGMA Table 9 assigns no PS3 (N/A) after discordant calibrated functional results across three studies.
vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:23108138 PMID:24123850
PS4 Not assessed Not assessed: no matched case-control counts, p-value, OR, or confidence interval are available to test the ENIGMA PS4 requirements.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:23108138 PMID:24123850
PM1 N/A Not applicable: residue 2842 lies in the DNA-binding domain, but ENIGMA explicitly marks PM1 Do not use and captures domain information under PP3/BP4.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:24323938
PM2 Not met Not met: the variant is observed in both specified non-cancer controls datasets, at 2/236574 and 1/147686 alleles, rather than absent.
cspec gnomad_v2 gnomad_v4
PM3 Not met Not met: the variant was homozygous, but the reported patient had isolated primary ovarian insufficiency without the VCEP-required Fanconi anemia phenotype.
cspec
PM4 N/A Not applicable: p.Arg2842Cys is a missense substitution with no protein-length change, and the ENIGMA specification explicitly says PM4 is not used.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A Not applicable: ENIGMA marks missense PM5 Do not use, and the separate PM5 route is restricted to PVS1 protein-termination-codon variants.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 PMID:23108138
PM6 N/A Not applicable: the ENIGMA VCEP explicitly prohibits PM6 because BRCA1/2-related cancers are relatively common and de novo predictive capacity is uncalibrated.
cspec vcep_specifications_v1_2_2024_11_18
PP1 Not assessed Not assessed: no quantitative co-segregation likelihood ratio, affected-relative meioses, or variant-specific PP1 segregation entry is available for applying the 2.08:1 threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001
PP2 N/A Not applicable: ENIGMA explicitly marks PP2 Do not use because missense variants are not a common BRCA1/BRCA2 pathogenicity mechanism.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Met Met at Supporting: BayesDel no-AF 0.371621 meets the ENIGMA BRCA2 PP3 protein-impact threshold of >=0.30 in the DNA-binding domain.
cspec vcep_supplementarytables_v1_2_2024_11_18 bayesdel spliceai
PP4 N/A Not applicable: Li et al. clinical-history LR 0.6383 fails the ENIGMA PP4 requirement, 0.6383007708778127 ≥ 2.08? no.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5 N/A Not applicable: the ENIGMA BRCA2 specification explicitly says PP5 is not used.
cspec vcep_specifications_v1_2_2024_11_18
BA1 Not met Not met: maximum reported non-cancer subgroup AF is 7.96813e-05, below the ENIGMA BA1 threshold of 0.001.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: gnomAD v3.1 non-cancer grpmax FAF is 0, while gnomAD v2.1 reports no FAF for its highest raw subgroup AF of 7.96813e-05.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: zero gnomAD homozygotes do not provide the phenotyped individual-level observations required for ENIGMA BS2 point assignment.
cspec gnomad_v2 gnomad_v4
BS3 Not met Not met: ENIGMA Table 9 assigns no BS3 (N/A) because calibrated functional studies produced discordant results rather than consistent benign function.
vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:23108138 PMID:24123850
BS4 Not assessed Not assessed: no quantitative non-segregation likelihood ratio, affected-relative meioses, or variant-specific BS4 entry is available for applying the 0.48:1 threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1 Not met Not met: SpliceAI max delta 0.051 is within the ≤0.1 limit, but Arg2842 lies inside the ENIGMA DNA-binding domain aa 2481-3186.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:24123850
BP2 N/A Not applicable: the ENIGMA BRCA2 specification says BP2 is not used and is applied only in the context of BS2.
cspec
BP3 N/A Not applicable: p.Arg2842Cys is not an in-frame insertion or deletion, and ENIGMA explicitly marks BP3 as not to use for BRCA2.
cspec vcep_specifications_v1_2_2024_11_18
BP4 Not met Not met: SpliceAI 0.051 is <=0.1, but BayesDel no-AF 0.371621 exceeds the ENIGMA BRCA2 BP4 no-impact cutoff of 0.18.
cspec vcep_supplementarytables_v1_2_2024_11_18 bayesdel spliceai
BP5 N/A Not applicable: Li et al. clinical-history LR 0.6383 fails BP5's ≤0.48 threshold, 0.6383007708778127 ≤ 0.48? no.
cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6 N/A Not applicable: the ENIGMA BRCA2 specification explicitly says BP6 is not used.
cspec vcep_specifications_v1_2_2024_11_18
BP7 N/A Not applicable: p.Arg2842Cys is a missense variant inside the BRCA2 DNA-binding domain, whereas BP7 covers silent/intronic variants or missense variants outside that domain.
cspec
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