The c.3549C>A (p.Tyr1183Ter) variant in PALB2 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes amino acids 1183-1186) in a gene where loss-of-function is an established disease mechanism. This variant, or another variant leading to the same protein truncation, has been detected in three individuals with autosomal recessive FANCN. Of those individuals, three were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and three of those were confirmed in trans by parental testing (co-occurring variants: c.2257C>T (p.Arg753Ter); c.2962C>T (p.Gln988Ter); c.3116delA (p.Asn1039Ilefs*2): PMID 17200671). The variant has been reported to segregate with breast and/or pancreatic cancer in 15 affected members from 6 families (Invitae; Ambry Genetics). This variant is non-functional in multiple different protein assays (PMID 31757951, PMID 31636395); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. 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, PP1_Strong, PM3_Strong)