NM_000059.3:c.3881T>G (p.Leu1294Ter) is a nonsense variant in BRCA2 exon 11 that introduces a premature termination codon at residue 1294 of 3418, predicted to result in loss of the C-terminal DNA-binding domain and nuclear localization signals.¹ PVS1 (Very Strong) is met per ENIGMA Specifications Table 4, which assigns PVS1 to BRCA2 exon 11 PTC variants. Loss of function is the established disease mechanism for BRCA2.² PM5_Strong (PTC) is met per ENIGMA Table 4, which assigns PM5_Strong (PTC) for BRCA2 exon 11 termination codon variants. Exon 11 harbors numerous proven pathogenic PTC variants.³ PM2_Supporting is met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare pathogenic variant in outbred populations.⁴ The variant has been classified as Pathogenic by the ENIGMA expert panel and 7 clinical laboratories in ClinVar (VariationID: 266780).⁵ Under ENIGMA Table 3 combining rules, PVS1 (Very Strong) + PM5_Strong + PM2_Supporting meets the criteria for Pathogenic classification (1 Very Strong + 1 Strong fulfills the Pathogenic threshold).⁶