NM_024675.4:c.1652A>G (p.Tyr551Cys) is a missense variant in PALB2, a gene where loss of function is an established disease mechanism for PALB2-related cancer predisposition (autosomal dominant) and Fanconi anemia complementation group N (autosomal recessive).¹ The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 across all populations, meeting the CSPEC PM2_Supporting threshold of ≤ 0.000333% allele frequency (PM2_Supporting).² CSPEC PALB2 v1.2.0 applies BP1 (Supporting) to all missense variants, based on evidence that PALB2 has a very low rate of functional missense variants and true pathogenic missense changes are thought to be exceedingly rare (BP1_Supporting).³ Multiple CSPEC criteria are explicitly not applicable to PALB2 missense variants: PS1, PM1, PM5, PP2, PP3, and BP4 are all prohibited by VCEP rules because missense pathogenic variation is not yet confirmed as a disease mechanism for PALB2.⁴ PS3 and BS3 (functional studies) are marked not applicable by CSPEC; PS2 and PM6 (de novo) are not applicable; PP4 (phenotype specificity) and PP5 (reputable source) are not applicable for this VCEP; BP2, BP5, BP6, and BP7 are not applicable for this variant type.⁵ PS4 (case-control), PP1 (co-segregation), BS2 (FA probands), and BS4 (lack of segregation) could not be assessed due to absence of clinical proband, segregation, or case-control data in the evidence set.⁶ The variant has been reported in ClinVar as Uncertain Significance (VCV000856757) by 3 clinical laboratories with review status 'criteria provided, single submitter.' No expert panel classification is available.⁷ No variant-specific functional or clinical evidence was identified in the literature. All PMIDs associated with this ClinVar entry are general guidelines or review articles (ACMG/AMP standards, genetic counseling recommendations, USPSTF statements) that do not mention NM_024675.4:c.1652A>G or p.Tyr551Cys.⁸ Criterion summary: one pathogenic supporting criterion met (PM2_Supporting) and one benign supporting criterion met (BP1_Supporting). Per ACMG/AMP 2015 combining rules adopted by the CSPEC PALB2 framework (Rule31), the presence of both benign supporting and pathogenic supporting evidence results in a classification of Uncertain Significance with conflicting evidence.⁹