NM_024675.4:c.2580G>T (p.Glu860Asp) is a missense variant in PALB2, a gene where loss of function is an established mechanism of disease but missense pathogenicity is not yet confirmed.¹ The variant is absent from gnomAD v2.1 and v4.1, meeting the VCEP PM2_Supporting criterion (frequency ≤ 0.000333%).² Per VCEP PALB2 specification, BP1_Supporting is applied to all missense variants given the very low likelihood that missense variants in PALB2 are pathogenic.³ Multiple VCEP criteria are not applicable to missense variants in PALB2: PVS1, PS1, PM1, PM5, PP2, PP3, BP4. Additional criteria (PS3, BS3, PS2, PM6, PP4, PP5, BP2, BP5, BP6) are not applicable per VCEP specification.⁴ SpliceAI predicts no splice impact (max delta 0.01). REVEL score (0.021) and BayesDel score (-0.521846) are consistent with a benign computational prediction for the missense change, though not formally applied as criteria per VCEP rules.⁵ ClinVar reports this variant as Uncertain significance (4 clinical laboratories) and Likely benign (1 clinical laboratory). No expert panel classification is available.⁶ With PM2_Supporting (1 pathogenic supporting point) and BP1_Supporting (1 benign supporting point), the variant falls into the Uncertain Significance category per ACMG/AMP 2015 combination rules (Rule 31: conflicting supporting evidence).⁷