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A systematic review of predicted pathogenic PALB2 variants: an analysis of mutational overlap between epithelial cancers.

Accepted version
Peer-reviewed

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Article

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Authors

Janssen, Boris 
Bellis, Sarah 
Koller, Thomas 
Liau, Siong-Seng 

Abstract

Partner and localiser of BRCA2 forms part of a macromolecular complex with BRCA1 and BRCA2, which is critical for the repair of double-strand DNA breaks by homologous DNA recombination. Germline loss-of-function variants in the PALB2 gene may confer an increased lifetime risk of breast, pancreatic, ovarian and other cancers. However, the complete spectrum of predicted pathogenic PALB2 variants associated with each tissue type of cancer remains unknown. A systematic review is performed with the aim of cataloguing predicted pathogenic PALB2 variants in breast, ovary and pancreas cancers. All catalogued predicted pathogenic variants are analysed to assess for overlap and mutational "hotspots" within gene exons. Our results showed that 911 (92.5%) cases were described in breast cancer patients, 49 (5.0%) cases were described in ovarian cancer patients, and 24 (2.4%) cases were described in pancreatic cancer patients. The top five most frequently reported predicted pathogenic PALB2 variants were c.509_510delGA, c.3113G > A, c.1592delT, c.172_175delTTGT, and c.1240C > T, accounting for 57.3% of all cases. Breast and pancreatic cancers share five variants while breast and ovarian cancers share 12 variants. Breast, ovarian and pancreatic cancers share eight common variants. Exons with the highest mutation rates were exons 2 (6.7%), 1 (6.3%) and 3 (5.8%). This systematic review provides a quantitative catalogue of predicted pathogenic PALB2 variants described in cancers. This comprehensive analysis of the PALB2 mutational spectrum represents a useful resource for clinicians overseeing PALB2-related cancer surveillance and provides a valuable resource for future PALB2-specific research.

Description

Keywords

BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Carcinoma, Ovarian Epithelial, Exons, Fanconi Anemia Complementation Group N Protein, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Ovarian Neoplasms, Pancreatic Neoplasms

Journal Title

J Hum Genet

Conference Name

Journal ISSN

1434-5161
1435-232X

Volume Title

65

Publisher

Springer Science and Business Media LLC
Sponsorship
MRC (G1002543)
Medical Research Council (G1002543)