LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-12
Case ID: NM_000059.4_BRCA2_c.8394_8396delinsAA_20261112_145738
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4(BRCA2):c.8394_8396delinsAA

BRCA2  · NP_000050.3:p.(Arg2799AsnfsTer22)  · NM_000059.4
GRCh37: chr13:32944601 TAG>AA  ·  GRCh38: chr13:32370464 TAG>AA
Gene: BRCA2 Transcript: NM_000059.4
Final call
Pathogenic
PVS1 very strong PM5 strong PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Arg2799AsnfsTer22)
gnomAD AF
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PVS1 (very strong) is supported by the exon 19 frameshift producing p.Arg2799AsnfsTer22.
2
Pathogenic: PM5 (strong) is preassigned by ENIGMA Table 4 for BRCA2 exon 19 PTC variants.
3
Pathogenic: PP5 (supporting) is recorded from the ENIGMA expert-panel pathogenic classification, but is not needed for the final rule.
Final determination: Under ENIGMA BRCA2 Version 1.2 Table 3, one Very Strong pathogenic criterion plus at least one Strong pathogenic criterion yields Pathogenic.
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 Met Met: ENIGMA Table 4 assigns full PVS1 to BRCA2 exon 19 PTC variants, and this variant is a frameshift producing p.Arg2799AsnfsTer22.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS1 N/A Not applicable: the variant is a frameshift, whereas ENIGMA PS1 applies to same-missense or same-predicted-splicing variants.
cspec vcep_specifications_v1_2_2024_11_18
PS2 N/A Not applicable: the ENIGMA BRCA2 VCEP does not permit PS2 because de novo occurrence has not been calibrated for these relatively common cancers.
cspec vcep_specifications_v1_2_2024_11_18
PS3 Not assessed Not assessed: no exact-variant protein functional assay or pre-assigned Table 9 code was found in the five governing VCEP files.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 PMID:22632462
PS4 Not assessed Not assessed: no variant-specific case-control counts, odds ratio, p-value, or confidence interval were available to test the PS4 thresholds.
cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 clinvar
PM1 N/A Not applicable: ENIGMA explicitly prohibits PM1 and routes domain evidence through PP3/BP4, despite residue 2799 lying within DNA-binding aa 2481-3186.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 N/A Not applicable: ENIGMA excludes delins variants from PM2, despite the exact variant being absent from gnomAD v2.1 and v3.1 non-cancer datasets.
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, second pathogenic BRCA2 variant, phase, or PM3 point total was available for this frameshift.
vcep_specifications_v1_2_2024_11_18
PM4 N/A Not applicable: the ENIGMA BRCA2 specification says PM4 is not used and captures protein-length analysis through PP3/BP4 instead.
cspec vcep_specifications_v1_2_2024_11_18
PM5 Met Met, Strong: ENIGMA Table 4 preassigns PM5_Strong (PTC) for BRCA2 exon 19, where this genomic frameshift creates a termination codon.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Not applicable: the ENIGMA BRCA2 VCEP does not permit PM6 because de novo occurrence has not been calibrated for these relatively common cancers.
cspec vcep_specifications_v1_2_2024_11_18
PP1 Not assessed Not assessed: no quantitative co-segregation likelihood ratio or family-level genotype and phenotype data are available to compare with the VCEP's LR ≥2.08:1 threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PP2 N/A Not applicable: ENIGMA does not use PP2 for BRCA2, and this variant is a frameshift rather than a missense variant.
cspec vcep_specifications_v1_2_2024_11_18
PP3 N/A Not applicable: the ENIGMA PP3 rule covers missense, in-frame, silent, or eligible intronic variants, whereas this variant is a frameshift.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP4 Not assessed Not assessed: the Li et al. clinical-history table has no c.8394_8396delinsAA row from which to calculate or assign a PP4 likelihood-ratio strength.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_pmid_31853058_li_2020_geneticsinmedicine vcep_pmid_31853058_methods_supplement vcep_pmid_17924331_easton_2007_ajhg
PP5 Met Not applicable: the ENIGMA BRCA2 specification explicitly states that PP5 is not to be used.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
BA1 Not met Not met: the exact variant is absent from gnomAD v2.1 and v4.1, so no filter allele frequency exceeds the ENIGMA BA1 threshold of 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 exact variant is absent from the relevant gnomAD datasets, providing no FAF above the ENIGMA BS1 Supporting threshold of 0.00002.
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 phenotyped trans, homozygous, age, or follow-up observation is available for the ENIGMA BS2 point system.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS3 Not assessed Not assessed: no exact-variant benign protein-function assay or pre-assigned Table 9 code was found in the five governing VCEP files.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 PMID:22632462
BS4 Not assessed Not assessed: no quantitative non-segregation likelihood ratio or affected-relative genotype and phenotype data are available to compare with the VCEP's LR ≤0.48:1 threshold.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1 N/A Not applicable: BP1 covers silent, missense, or in-frame indel variants, whereas this variant is a frameshift.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP2 N/A Not applicable: ENIGMA BRCA2 explicitly says BP2 is not used and limits it to the BS2 context.
vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: BP3 is a criterion the ENIGMA specification says not to use, and this variant is a frameshift.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: ENIGMA BP4 is restricted to missense/in-frame, silent, or eligible intronic variants, and this variant is a frameshift.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP5 Not assessed Not assessed: no variant-level clinical likelihood ratio was found to test the BP5 supporting threshold LR ≤0.48:1 or stronger thresholds.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_pmid_17924331_easton_2007_ajhg
BP6 N/A Not applicable: the ENIGMA BRCA2 specification explicitly states that BP6 is not to be used.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
BP7 N/A Not applicable: ENIGMA BP7 is restricted to silent or eligible intronic variants with BP4 met, whereas this variant is a frameshift.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
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