The c.3350G>A variant in PALB2 is a missense variant predicted to cause substitution of arginine by lysine at amino acid 1117 (p.Arg1117Lys); however, RNA analysis demonstrated that the variant impacts splicing, leading to exon 12 skipping (r.3202_3350del149, p.Gly1068ValfsTer5) and a translational frameshift with 100% allele bias and no wild-type splice events harboring the variant (Ambry Genetics). The resulting mRNA is not predicted to undergo nonsense-mediated decay, but impacts the WD40 domain, which is a functionally important region. This variant is absent from gnomAD v2.1.1. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (PALB2 p.Tyr1183*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been observed in combination with a PALB2 exon 11 duplication, which is classified as pathogenic, in at least four adult individuals without Fanconi Anemia (Ambry Genetics and Invitae). Although the phase of the variants was not confirmed, evidence from these individuals was not used to apply BS2 on the basis that multiple co-occurrences of this variant with the exon 11 duplication in unrelated individuals suggests these variants are more likely to be in cis. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1(RNA), PM2_Supporting, PM5_Supporting)