LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-08
Case ID: NM_000059.4_c.7092_7099del_20260708_130222
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.7092_7099del

BRCA2  · NP_000050.3:p.(Glu2364AspfsTer25)  · NM_000059.4
GRCh37: chr13:32929078 ATGAACATC>A  ·  GRCh38: chr13:32354941 ATGAACATC>A
Gene: BRCA2 Transcript: NM_000059.4
Final call
Pathogenic
PVS1 very strong PM5 strong PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Glu2364AspfsTer25)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_000059.4:c.7092_7099del (p.Glu2364AspfsTer25) is an 8 bp frameshift deletion in BRCA2 exon 14 that creates a premature termination codon, removing the DNA-binding domain (aa 2481–3186) and nuclear localization signals. It is classified as Pathogenic under ENIGMA BRCA1/2 v1.2.0.
2
PVS1 (very strong) is applied: ENIGMA Table 4 assigns full PVS1 weight to protein termination codon variants in BRCA2 exon 14. The frameshift is predicted to undergo nonsense-mediated decay and eliminates all C-terminal functional domains.
3
PM5_PTC (strong) is applied: ENIGMA Table 4 assigns PM5_Strong (PTC) for exon 14 based on the presence of proven pathogenic PTC variants in this exon, providing additional weight beyond PVS1.
4
PM2 (supporting) is applied: the variant is absent from gnomAD v2.1 (exome, non-cancer), v4.1 (non-cancer), and gnomAD-Canada, meeting the ENIGMA PM2_Supporting threshold.
5
This combination (PVS1 + PM5_PTC Strong + PM2 Supporting) satisfies the ENIGMA Table 3 rule for Pathogenic: 1 Very Strong + ≥1 Strong criterion.
Final determination: ENIGMA BRCA1/2 v1.2.0 Table 3 Pathogenic rule: 1 Very Strong criterion (PVS1) AND >=1 Strong criterion (PM5_PTC) 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 NM_000059.4:c.7092_7099del is an 8 bp frameshift deletion in BRCA2 exon 14 (c.7008–7435), predicted to produce a premature termination codon at p.(Glu2364AspfsTer25). Loss of function is a well-established disease mechanism for BRCA2. Under ENIGMA BRCA1/2 v1.2.0 Specifications Table 4, protein termination codon (PTC) variants in exon 14 are assigned PVS1 at very strong weight. The truncation occurs upstream of the BRCA2 DNA-binding domain (aa 2481–3186), and the variant is expected to undergo nonsense-mediated decay. No SpliceAI-predicted splicing impact (max delta = 0.01) complicates the null interpretation.
cspec vcep_specifications_table4_v1_2_2024_11_18
PS1 N/A ENIGMA PS1 applies to missense substitutions with a previously classified pathogenic comparator, or to exonic/intronic variants with the same predicted splice impact as a known pathogenic variant. NM_000059.4:c.7092_7099del is a frameshift deletion; neither comparator category applies.
PS2 N/A ENIGMA BRCA1/2 v1.2.0 specification lists PS2 as Not Applicable (de novo criterion not used in this framework).
PS3 Not assessed No variant-specific functional assay data are available for NM_000059.4:c.7092_7099del. ENIGMA Specifications Table 9 (curated functional assay results) does not include this variant. Table 9 is primarily calibrated for missense and synonymous variants; this frameshift null variant is already captured by PVS1 and PM5_PTC.
vcep_specifications_table9_v1_2_2024_11_18
PS4 Not assessed No case-control study data are available for this variant. The variant is absent from the ENIGMA posterior probability reference set (Supplementary Table 7) and from the Parsons et al. 2019 multifactorial dataset (HUMU-40-1557-s001). No case-control odds ratio or p-value can be computed.
vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS5 N/A PS5 is not defined in the ENIGMA BRCA1/2 v1.2.0 specification criteria set.
PM1 N/A ENIGMA BRCA1/2 v1.2.0 specification lists PM1 as Not Applicable. Hotspot/domain criteria are not independently used for BRCA2 under this framework.
PM2 Met Under ENIGMA PM2_Supporting, the variant is absent from gnomAD v2.1 (non-cancer, exome only) and gnomAD v4.1 (non-cancer) in all outbred populations. This meets the ENIGMA threshold for PM2 at supporting strength.
gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3 N/A PM3 was explicitly skipped per adjudication instructions.
PM4 N/A ENIGMA BRCA1/2 v1.2.0 specification lists PM4 as Not Applicable. Protein-length changes are addressed through PVS1 and PM5_PTC instead.
PM5 Met ENIGMA Specifications Table 4 assigns PM5_Strong (PTC) for protein termination codon variants in BRCA2 exon 14. This exon is not among the PM5_N/A exons (E6, E12, E27). A proven pathogenic PTC variant has been observed in this exon previously, justifying the additional weight beyond PVS1.
cspec vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A ENIGMA BRCA1/2 v1.2.0 specification lists PM6 as Not Applicable (de novo criterion not used in this framework).
PP1 Not assessed No segregation data are available for this variant. ENIGMA PP1 requires a quantitative cosegregation likelihood ratio (LR ≥ 2.08 for supporting, ≥ 4.3 for moderate, ≥ 18.7 for strong). No pedigree or cosegregation analysis has been performed.
PP2 N/A ENIGMA BRCA1/2 v1.2.0 specification lists PP2 as Not Applicable.
PP3 N/A ENIGMA PP3 applies to missense or in-frame insertion/deletion variants inside a clinically important functional domain with BayesDel ≥ 0.30, or to variants with predicted splicing impact (SpliceAI ≥ 0.2). NM_000059.4:c.7092_7099del is a frameshift deletion with SpliceAI max delta = 0.01. Neither criterion is met. Furthermore, ENIGMA guidance specifies not to stack PP3 when PVS1 is already applied for the same evidence stream.
spliceai cspec
PP4 Not assessed The variant was not found in Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio table for BRCA2. ENIGMA PP4 requires an LR ≥ 2.08 from multifactorial clinical data. No clinical-history LR is available for this variant.
vcep_pmid_31853058_brca2_clinical_history_lr
PP5 N/A ENIGMA BRCA1/2 v1.2.0 specification lists PP5 as Not Applicable.
BA1 Not met ENIGMA BA1 requires the variant to have a filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only) and/or v3.1 (non-cancer). This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
gnomad_v2 gnomad_v4 gnomad_canada
BS1 Not met ENIGMA BS1_Strong requires FAF > 0.0001 (0.01%), and BS1_Supporting requires FAF > 0.00002 (0.002%). This variant is absent from all gnomAD populations; neither threshold is met.
gnomad_v2 gnomad_v4
BS2 Not assessed ENIGMA BS2 requires a points-based assessment of the absence of Fanconi Anemia features in individuals homozygous or compound heterozygous for the variant. No proband phenotype data are available for this variant.
BS3 Not assessed ENIGMA BS3 applies to well-established functional studies showing no damaging effect on protein function. This is a frameshift null variant predicted to truncate the protein; BS3 is not biologically plausible for a PTC variant. The variant is not listed in ENIGMA Table 9 curated functional assay results.
vcep_specifications_table9_v1_2_2024_11_18
BS4 Not assessed ENIGMA BS4 requires a quantitative cosegregation LR ≤ 0.48 showing lack of segregation with disease. No segregation data are available for this variant.
BP1 N/A ENIGMA BP1 applies to silent substitutions, missense, or in-frame insertion/deletion variants outside a clinically important functional domain with no splicing predicted. NM_000059.4:c.7092_7099del is a frameshift deletion; not eligible for BP1.
BP2 N/A ENIGMA BRCA1/2 v1.2.0 specification lists BP2 as Not Applicable.
BP3 N/A ENIGMA BRCA1/2 v1.2.0 specification lists BP3 as Not Applicable.
BP4 N/A ENIGMA BP4 applies to missense or in-frame insertion/deletion variants inside a clinically important functional domain with no predicted impact (BayesDel ≤ 0.18 AND SpliceAI ≤ 0.1), or to silent/intronic variants with no splicing predicted. NM_000059.4:c.7092_7099del is a frameshift deletion; not eligible for BP4 under ENIGMA rules.
BP5 Not assessed The variant was not found in Li et al. 2020 (PMID:31853058) clinical-history LR table for BRCA2. ENIGMA BP5 requires an LR ≤ 0.48 from multifactorial clinical data. No clinical-history LR is available for this variant.
vcep_pmid_31853058_brca2_clinical_history_lr
BP6 N/A ENIGMA BRCA1/2 v1.2.0 specification lists BP6 as Not Applicable.
BP7 N/A ENIGMA BP7 applies to silent substitutions or intronic variants with no splicing predicted (meeting BP4), or to mRNA-level functional studies showing no damaging effect. NM_000059.4:c.7092_7099del is a frameshift deletion; not eligible for BP7.
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