NM_024675.3:c.82T>A (p.Tyr28Asn) is a missense variant in PALB2. It is absent from gnomAD v2.1 and v4.1, meeting PM2_Supporting per PALB2 VCEP v1.2.0 (allele frequency ≤ 0.000333%).¹ BP1_Supporting is applied as the PALB2 VCEP v1.2.0 assigns this criterion to all missense variants in PALB2, given that PALB2 has a low rate of functionally impactful missense variants and true pathogenic missense variants are thought to be exceedingly rare.² In silico predictors are not applied (PP3/BP4 not used for missense variants per VCEP). REVEL score is 0.219 and BayesDel score is 0.039. SpliceAI predicts no splice impact (max delta = 0.00).³ This variant has been reported in ClinVar (ID 410148) as Uncertain Significance by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP and by 3 clinical laboratories. No case-control studies, co-segregation data, or functional studies specific to this variant were identified.⁴ PVS1, PS1, PS3, PM1, PM5, PP2, PP3, PP4, PP5, BS3, BP2, BP4, BP5, BP6, and BP7 are not applicable per PALB2 VCEP v1.2.0 rules, predominantly because missense pathogenic variation is not yet confirmed as a disease mechanism for PALB2. PS2, PS4, PM6, PP1, BA1, BS1, BS2, and BS4 are not met due to absence of qualifying evidence.⁵ With PM2_Supporting (1 pathogenic supporting criterion) and BP1_Supporting (1 benign supporting criterion) in a VCEP framework with no other met criteria, the evidence is balanced between benign and pathogenic signals. The variant is classified as Uncertain Significance per the ACMG/AMP combining rules (Rule 31: ≥1 benign supporting + ≥1 pathogenic supporting → VUS with conflicting evidence). This is consistent with the ClinGen Expert Panel classification.⁶