ClinVar

Description

This variant is a gross deletion of the genomic region encompassing exons 12-13 of the PALB2 gene. The 5' boundary is likely confined to intron 11. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated PALB2 protein. Loss-of-function variants including gross deletions in PALB2 are known to be pathogenic. Deletion of exons 12-13 has been reported in the literature in an individual affected with breast and pancreatic cancer (PMID: 19635604). This deletion eliminates a portion of the WD40 functional domain, which is encoded by exons 7 to 13 of the PALB2 mRNA. The entire WD40 domain is known to be required for normal PALB2 protein function (PMID: 19423707, 16793542, 17200671) and loss-of-function mutations that disrupt this domain have been classified as pathogenic (Invitae). For these reasons, this sequence change has been classified as Pathogenic.