Submission Details

PALB2 encodes a protein that directly interacts with BRCA2. PALB2 was first reported in relation to autosomal dominant PALB2-related cancer predisposition in 2007 (Rahman et al., PMID: 17200668). PALB2-related cancer predisposition is characterized by a susceptibility to breast, ovarian, and pancreatic cancers. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern and phenotypic variability. Therefore, breast, ovarian, and pancreatic cancers have been lumped into this curation for the new disease entity MONDO:0700272 and the prior separate curations for hereditary breast and ovarian cancer and hereditary nonpolyposis colon cancer replaced by this updated curation. Fanconi anemia complementation group N (MONDO:0012565), an autosomal recessive disorder with unique clinical features was curated separately. The mechanism of disease is loss of function. Seventeen variants (nonsense, frameshift, large deletion, and missense) that have been reported in 17 probands in 8 publications (PMIDs: 17200668, 17420451, 30875412, 31858328, 28767289, 19264984, 30322717, 29053726) are included in this curation. In addition, several case-control studies have been curated which support the association of breast, ovarian, and pancreatic cancers with PALB2-related cancer predisposition (PMIDs: 26720728, 28888541, 33471974, 33471991, 29922827). More evidence is available in the literature, but the maximum score for genetic evidence (12 Points) has been reached. Please note, at least one case-control study supports an association of gastric cancer with PALB2-related cancer predisposition, but overall evidence for this association is still limited (PMID: 36988593). In addition, the association of PALB2 with colorectal cancer susceptibility was evaluated, and no significant evidence was found to support this gene-disease association (PMIDs: 33309985, 31841383). PALB2-related cancer predisposition is also supported by experimental evidence, including in vitro functional assays and animal models (4 Points, PMIDs: 31636395, 19369211, 19423707, 16793542, 33893322). This experimental evidence demonstrates that variants causing loss of function result in impaired interaction with BRCA2 and homologous recombination deficiencies. In summary, there is definitive evidence supporting the relationship between PALB2 and autosomal dominant PALB2-related cancer predisposition. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was evaluated as definitive for cancer predisposition by the Hereditary Cancer GCEP on 12/15/2023. Information regarding the colon cancer gene-disease association was evaluated on 5/24/2024 and approved by the ClinGen Hereditary Cancer GCEP (SOP Version 10). As a result of this re-evaluation, the overall classification for Definitive did not change for hereditary breast and ovarian cancer but were lumped into this new entity and HNPCC curation previously Limited was removed as data was no longer scorable.