NM_024675.4:c.205C>T (p.His69Tyr) is a missense variant in PALB2 exon 3. Under the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specification for PALB2 v1.2.0, missense variants are not a confirmed mechanism of disease.¹ BP1_Supporting is met: the VCEP applies BP1 to all PALB2 missense variants given the very low likelihood that missense variants are pathogenic.² PM2_Supporting is not applied: while the overall gnomAD v4.1 frequency (0.000124%) is below the VCEP threshold (≤0.000333%), the variant is observed in the East Asian subpopulation at 0.00223% (1/44,858 alleles), triggering the VCEP exception for under-represented sub-populations with frequency >0.0003%.³ The variant is present in gnomAD v4.1 at extremely low frequency (2/1,609,786 alleles; 0 homozygotes). It is absent from gnomAD v2.1.⁴ This variant has been reported in ClinVar (ID 245654) as Uncertain significance by 6 clinical laboratories and Likely benign by 2 clinical laboratories. No expert panel classification is available.⁵ SpliceAI predicts no splicing impact (max delta score 0.00). REVEL (0.053) and BayesDel (-0.387659) are consistent with a benign computational prediction, though in silico predictors are not used for PALB2 missense variants under this VCEP.⁶ Multiple criteria are not applicable under the PALB2 VCEP for missense variants: PVS1 (not a null variant), PS1 (missense excluded), PM1 (missense pathogenicity not confirmed), PM5 (missense excluded), PP2 (missense not confirmed), PP3 (missense excluded), BP4 (missense excluded), BP7 (missense excluded). PS2, PM6, PS3, BS3, PP4, PP5, BP2, BP5, BP6 are not applicable per VCEP specification.⁷ No variant-specific functional, segregation, case-control, or Fanconi Anemia proband data were identified in the reviewed literature or databases.⁸