NM_024675.4:c.1096A>G (p.Asn366Asp) is a missense variant in PALB2 with an extremely low population frequency in gnomAD v4.1 (total AF = 4.96e-06, 8/1,614,152 alleles, 0 homozygotes), meeting PM2_Supporting under the PALB2 VCEP threshold of ≤ 0.000333%.¹ Under the PALB2 HBOP VCEP v1.2, BP1 is applied at supporting benign level to all PALB2 missense variants. Missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease, and true missense pathogenic variants are thought to be exceedingly rare.² This variant has been reported in ClinVar as Uncertain significance by 5 clinical laboratories and Likely benign by 1 laboratory (VCV000188117), with an overall review status of 'criteria provided, single submitter.' No expert panel has reviewed this variant.³ SpliceAI predicts no splicing impact (max delta = 0.00). In silico missense predictors (REVEL = 0.046, BayesDel = -0.707777) lean toward benign, but the PALB2 VCEP does not permit the use of PP3 or BP4 for missense variants.⁴ The majority of ACMG criteria are not applicable under the PALB2 VCEP for missense variants: PVS1 (not a null variant), PS1/PS3/PM1/PP2 (missense pathogenic variation not confirmed), PS5 (not in VCEP), PM5 (truncation-only rule), PP3/BP4 (missense not used), PS2/PM6 (de novo not applicable), PP4/BP5 (not applicable per VCEP), BP7 (not synonymous), PP5/BP6 (not for use per VCEP).⁵ With one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP1), the evidence is balanced and insufficient to classify this variant as pathogenic or benign. The variant is classified as Uncertain Significance under PALB2 VCEP v1.2 combination rules.⁶