PVS1 (very strong): NM_004656.4:c.376_382del is a frameshift deletion in BAP1 exon 6, creating a premature termination codon at p.S126Dfs*59 with predicted NMD. BAP1 loss-of-function is the established germline disease mechanism for BAP1 tumor predisposition syndrome (PMID:35051358, PMID:35348477, PMID:39842618). NM_004656.4 is the MANE Select transcript.¹ PM2 (supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with a rare pathogenic variant.² Classification: Likely Pathogenic. Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): PVS1 (Very Strong) is met and PM2 (Supporting) is met. This combination of 1 Very Strong and 1 Supporting criterion does not satisfy the formal threshold for Pathogenic (which requires 1 Very Strong + ≥2 Supporting or ≥1 Strong). However, a frameshift null variant in a gene with established LoF disease mechanism, absent from all population databases, is classified as Likely Pathogenic per clinical practice. Per ACMG/AMP 2015, the evidence falls between formal Likely Pathogenic and Pathogenic thresholds; classification is Likely Pathogenic with a note that additional supporting evidence would elevate to Pathogenic.³