LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-19
Case ID: NM_000059.4_c.8107dup_20261019_124412
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.8107dup

BRCA2  · NP_000050.3:p.(Thr2703AsnfsTer3)  · NM_000059.4
GRCh37: chr13:32937443 G>GA  ·  GRCh38: chr13:32363306 G>GA
Gene: BRCA2 Transcript: NM_000059.4
Final call
Pathogenic
PVS1 very strong PM5 strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Thr2703AsnfsTer3)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 Very Strong: the exon 18 frameshift creates a premature stop upstream of the ENIGMA NMD escape boundary.
2
PM5 Strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to genomic premature termination codons in BRCA2 exon 18.
Final determination: Under ENIGMA BRCA2 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, very strong: c.8107dup is an exon 18 frameshift with a premature stop at p.2705, upstream of the VCEP's c.9600 NMD escape boundary.
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: c.8107dup is a frameshift, whereas the VCEP PS1 paths require a predicted missense substitution or a matched splicing event.
vcep_specifications_v1_2_2024_11_18 cspec
PS2 N/A Not applicable: the VCEP says de novo occurrences lack calibrated predictive capacity for BRCA1/2-related cancers and explicitly says not to use PS2.
cspec vcep_specifications_v1_2_2024_11_18
PS3 Not assessed Not assessed: no variant-specific calibrated assay result or pre-assigned PS3 code was found for BRCA2 c.8107dup in the governing ENIGMA sources.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4 Not assessed Not assessed: no variant-specific case-control p-value, odds ratio, and confidence interval were available to evaluate the ENIGMA PS4 requirements.
cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:31131967 vcep_specifications_v1_2_2024_11_18
PM1 N/A Not applicable: residue 2703 lies within the DNA-binding domain aa 2481-3186, but ENIGMA explicitly says PM1 is not used.
vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 cspec
PM2 N/A Not applicable: the VCEP excludes insertion-type indels from PM2, and c.8107dup is a frameshift duplication.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2
PM3 Not assessed Not assessed: no Fanconi Anemia phenotype, BRCA2 co-variant, phase, or PM3 point observations are available for this variant.
cspec vcep_specifications_v1_2_2024_11_18
PM4 N/A Not applicable: PM4 covers in-frame length changes or stop-loss variants, whereas c.8107dup is a frameshift with a premature termination codon.
cspec vcep_specifications_v1_2_2024_11_18
PM5 Met Met, Strong: ENIGMA Table 4 preassigns PM5_Strong (PTC) to BRCA2 exon 18, where this genomic frameshift creates a premature termination codon.
vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 cspec
PM6 N/A Not applicable: the VCEP says de novo occurrences lack calibrated predictive capacity for BRCA1/2-related cancers and explicitly says not to use PM6.
cspec vcep_specifications_v1_2_2024_11_18
PP1 Not assessed Not assessed: no quantitative co-segregation LR or affected-family segregation data is available to compare with the PP1 threshold of LR ≥2.08:1.
cspec vcep_specifications_v1_2_2024_11_18
PP2 N/A Not applicable: ENIGMA says not to use PP2, and this variant is a frameshift rather than a missense change.
vcep_specifications_v1_2_2024_11_18 cspec
PP3 N/A Not applicable: PP3 covers missense, in-frame, silent, or qualifying intronic variants, whereas c.8107dup is a frameshift.
cspec spliceai
PP4 Not assessed Not assessed: the required BRCA2 clinical-history table has no row for this variant, so no combined clinical likelihood ratio can be compared with PP4 thresholds.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5 N/A Not applicable: the ENIGMA BRCA2 specification explicitly says PP5 is not for use, and no ClinVar record was found for this variant.
cspec
BA1 Not assessed Not assessed: the variant is absent from both required non-cancer datasets, but FAF, read depth, and quality-control values needed for BA1 are unavailable.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2
BS1 Not assessed Not assessed: both required non-cancer datasets report absence, but FAF, read depth, and quality-control values needed for BS1 are unavailable.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2
BS2 Not assessed Not assessed: no qualifying healthy-adult observation or ENIGMA BS2 point assignment is available for this variant.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS3 Not assessed Not assessed: no variant-specific calibrated assay result or pre-assigned BS3 code was found for BRCA2 c.8107dup in the governing ENIGMA sources.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4 Not assessed Not assessed: no quantitative non-segregation LR or affected-family data is available to compare with the BS4 Supporting threshold of LR ≤0.48:1.
cspec vcep_specifications_v1_2_2024_11_18
BP1 N/A Not applicable: BP1 covers silent, missense, or in-frame variants outside domains, whereas c.8107dup is a frameshift.
vcep_specifications_v1_2_2024_11_18 cspec
BP2 N/A Not applicable: the ENIGMA BRCA2 specification says BP2 is not used and is applied only in the context of BS2.
cspec vcep_specifications_v1_2_2024_11_18
BP3 N/A Not applicable: BP3 covers in-frame changes in nonfunctional repetitive regions, whereas c.8107dup is a protein-truncating frameshift.
cspec vcep_specifications_v1_2_2024_11_18
BP4 N/A Not applicable: BP4 covers missense, in-frame, silent, or qualifying intronic variants, whereas c.8107dup is a frameshift.
cspec spliceai
BP5 Not assessed Not assessed: no variant-level combined clinical likelihood ratio was found for comparison with the ENIGMA BP5 <=0.48:1 supporting threshold.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6 N/A Not applicable: the ENIGMA BRCA2 specification explicitly says BP6 is not for use, and no ClinVar record was found for this variant.
cspec
BP7 N/A Not applicable: BP7 covers silent, intronic, or missense/in-frame variants, whereas c.8107dup is a frameshift.
cspec spliceai
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