NM_024675.4:c.3044C>T (p.Thr1015Ile) is a missense variant in PALB2, a gene in which loss-of-function is an established mechanism for autosomal dominant hereditary breast, ovarian, and pancreatic cancer predisposition.¹ This variant is present in gnomAD v4.1 at a total allele frequency of 0.00099% (16/1,614,014 alleles; grpmax FAF 0.000803%), predominantly in the European (non-Finnish) subpopulation. It is also present in gnomAD v2.1 at 0.00119% (3/251,446 alleles) and is absent from gnomAD-Canada.² This variant has been reported in ClinVar as Uncertain significance by 6 clinical laboratories and as Likely benign by 1 laboratory (ClinVar Variation ID 141554). No expert panel classifications are available.³ In silico predictors yield mixed results: REVEL score 0.238 (below the 0.5 threshold commonly used for deleterious prediction), BayesDel score -0.308 (below the 0.0 threshold for benign prediction), and SpliceAI max delta 0.00 (no predicted splicing impact).⁴ PALB2 VCEP BP1_Supporting is met: this criterion applies to all missense variants in PALB2 because true pathogenic missense variants are thought to be exceedingly rare, per the ClinGen HBOP VCEP v1.2.0.⁵ PALB2 VCEP PM2_Supporting is not met: the variant frequency in gnomAD v4 (0.00099%) exceeds the VCEP threshold of ≤0.000333%. BS1 and BA1 are also not met as the grpmax FAF (0.000803%) does not exceed either the BS1 (>0.01%) or BA1 (>0.1%) thresholds.⁶ Multiple PALB2 VCEP criteria are not applicable to missense variants by explicit VCEP rule: PVS1 (not a null variant), PS1, PM1, PM5, PP2, PP3, BP4, BP7. Additionally, PS2, PS3, PM6, PP4, PP5, BP2, BP3, BP5, BP6 are not applicable per VCEP framework.⁷ PS4, PP1, BS2, and BS4 could not be assessed due to absence of variant-specific case-control, segregation, or Fanconi Anemia proband data in the evidence reviewed. No reviewed publication (10 PMIDs screened, 5 full-text papers read) mentioned NM_024675.4:c.3044C>T. None of the ClinVar-submitted PMIDs contained variant-specific evidence for this missense.⁸ With only BP1_Supporting (supporting benign) met and no pathogenic criteria met, this variant is classified as Uncertain Significance (VUS) per ACMG/AMP 2015 combining rules. The single supporting benign criterion is insufficient for Likely Benign classification, which requires ≥2 supporting benign criteria or 1 strong benign + 1 supporting benign.⁹