This variant is a missense change (NM_024675.4:c.1351T>G, p.Leu451Val) in PALB2, a gene where loss of function is a known disease mechanism for PALB2-related cancer predisposition (autosomal dominant) and Fanconi anemia type FA-N (autosomal recessive).¹ In gnomAD v4.1, the variant is present at extremely low frequency (AF = 0.00031%, 5/1,614,074 alleles; grpmax FAF = 7.9e-07), meeting the PALB2 VCEP PM2_Supporting threshold (≤0.000333%).² BP1_Supporting is applied per PALB2 VCEP rule: all missense variants in PALB2 receive BP1 because missense pathogenic variation is not yet confirmed as a disease mechanism and true pathogenic missense variants are thought to be exceedingly rare.³ SpliceAI predicts no splicing impact (max delta = 0.00), and REVEL (0.027) and BayesDel (-0.741) scores are consistent with a benign in silico profile, though PP3 and BP4 are not applied to missense variants per VCEP rules.⁴ The variant has been observed in COSMIC in 2 somatic cancer samples but has no curated functional evidence from OncoKB.⁵ ClinVar reports this variant as Uncertain significance (VariationID 951843, 2 clinical laboratories, criteria provided single submitter) with no expert panel classification.⁶ No published literature specifically mentions NM_024675.4:c.1351T>G; all 16 PMIDs retrieved through ClinVar and literature searches were reviewed and none contain variant-specific evidence. All available full-text papers (PMID:34242744, 15604628, 17508274, 18163131) were confirmed to not mention this variant. No co-segregation data, case-control studies, de novo reports, or functional studies are available for this variant. PS4, PP1, BS2, BS4, and PVS1 remain not assessed due to absence of evidence. The only criteria met are PM2_Supporting (low population frequency) and BP1_Supporting (missense in PALB2). This yields a net of one pathogenic supporting and one benign supporting criterion — insufficient for classification beyond VUS per ACMG/AMP combination rules. The variant remains Uncertain significance.⁷