NM_000059.4:c.5946del is a frameshift deletion in BRCA2 exon 11 resulting in a premature termination codon (p.Ser1982ArgfsTer22) with expected nonsense-mediated decay, in a gene where loss of function is an established mechanism for hereditary breast and ovarian cancer. Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PVS1 at very strong weight.¹ ENIGMA Specifications Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 11, indicating additional pathogenic weight for a protein termination codon variant in an exon where other proven pathogenic PTC variants have been previously observed.² Clinical-history likelihood ratio analysis from Li et al. 2020 (PMID:31853058) yields an LR of 31.79 based on 149 carriers, exceeding the ENIGMA PP4_Strong threshold of ≥18.7:1. The personal and family cancer history profile of individuals carrying this variant is significantly enriched for breast and ovarian cancer compared to non-carriers.³ The variant is present in gnomAD population databases at low frequency in non-founder populations (grpmax FAF=5.39e-05 in v2.1, 2.154e-05 in v4.1), meeting ENIGMA BS1_Supporting (FAF >0.002% and ≤0.01%). The higher Ashkenazi Jewish allele frequency (0.589%) is attributable to a known founder effect and is excluded from BS1/BA1 assessment per ENIGMA non-founder population rules.⁴ This variant has been reported in ClinVar as Pathogenic by 67 clinical laboratories and by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel (ClinVar Variation ID: 9325). The variant has been observed in multiple affected individuals across diverse populations and has been described as a recurrent pathogenic founder mutation.⁵ Under ENIGMA Table 3 combining rules, the combination of PVS1 (Very Strong) + PM5 (Strong) satisfies the Pathogenic classification threshold (1 Very Strong + ≥1 Strong). PP4 (Strong) provides additional corroborating evidence. BS1_Supporting does not alter the pathogenic classification.⁶