NM_002691.4:c.2716_2717del (NP_002682.2:p.(Arg906AspfsTer47)) is a frameshift variant in exon 21 of 27 coding exons of POLD1. The deletion is predicted to cause a premature termination codon subject to nonsense-mediated decay, meeting PVS1 at very strong strength under the ClinGen SVI framework (PMC6185798). POLD1 loss of function is an established germline disease mechanism for polymerase proofreading-associated polyposis and cancer predisposition.¹ The variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency 0.00%), meeting PM2 at supporting strength under generic ACMG/AMP 2015 criteria (threshold <0.1%).² No additional pathogenic criteria are met. The variant is absent from ClinVar, has no published functional data, no de novo reports, no segregation data, and no case-control evidence. SpliceAI predicts no splice impact (max delta = 0.04). OncoKB shows Unknown Oncogenic Effect. No cancerhotspots.org hotspot at this residue. No benign criteria are met.³ Under the generic ACMG/AMP 2015 combination rules (PMID:25741868), PVS1 (very strong) with only one supporting criterion (PM2) does not formally reach the Likely Pathogenic threshold (requires 1 very strong + 1 moderate, or 1 strong + 1-2 moderate, etc.). However, a frameshift variant in a known tumor suppressor gene, absent from all population databases, is strongly indicative of pathogenicity. Many clinical laboratories would classify this as Likely Pathogenic using professional judgment. Formal classification under the strict combination rules is Variant of Uncertain Significance (VUS).⁴