PALB2 Variants: Protein Domains and Cancer Susceptibility

Trends Cancer. 2021 Mar;7(3):188-197. doi: 10.1016/j.trecan.2020.10.002. Epub 2020 Nov 1.

Abstract

Since its discovery, partner and localizer of breast cancer 2 (BRCA2) (PALB2) has emerged as a major tumor suppressor gene linked to breast cancer (BC), pancreatic cancer (PC), and ovarian cancer (OC) susceptibility. Its protein product plays a pivotal role in the maintenance of genome integrity. Here we discuss the first functional evaluation of a large set of PALB2 missense variants of uncertain significance (VUSs). Assessment of 136 VUSs interrogating a range of PALB2 biological functions resulted in the identification of 15 variants with consistent loss of function across different assays. All loss-of-function variants are located at the PALB2 coiled coil (CC) or at the WD40 domain, highlighting the importance of modular domains mechanistically involved in the DNA damage response (DDR) and pinpointing their roles in tumor suppression.

Keywords: PALB2; breast cancer; genetic testing; ovarian cancer; protein modular domains; susceptibility genes; tumor suppressor; variants of uncertain significance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Fanconi Anemia Complementation Group N Protein / genetics*
  • Genes, Tumor Suppressor*
  • Genetic Predisposition to Disease*
  • Humans
  • Loss of Function Mutation
  • Mutation, Missense
  • Neoplasms / genetics*
  • Protein Domains / genetics
  • Recombinational DNA Repair

Substances

  • Fanconi Anemia Complementation Group N Protein
  • PALB2 protein, human