Functional consequences of a rare missense BARD1 c.403G>A germline mutation identified in a triple-negative breast cancer patient

Breast Cancer Res. 2021 May 1;23(1):53. doi: 10.1186/s13058-021-01428-5.


We identified a rare missense germline mutation in BARD1 (c.403G>A or p.Asp135Asn) as pathogenic using integrated genomics and transcriptomics profiling of germline and tumor samples from an early-onset triple-negative breast cancer patient who later was administrated with a PARP inhibitor for 2 months. We demonstrated in cell and mouse models that, compared to the wild-type, (1) c.403G>A mutant cell lines were more sensitive to irradiation, a DNA damage agent, and a PARP inhibitor; (2) c.403G>A mutation inhibited interaction between BARD1 and RAD51 (but not BRCA1); and (3) c.403G>A mutant mice were hypersensitive to ionizing radiation. Our study shed lights on the clinical interpretation of rare germline mutations of BARD1.

Keywords: BARD1; DNA damage; Functional assay; Integrated genomics profiling; Irradiation; PARP inhibitor; Rare mutation; Triple-negative breast cancer; c.403G>A; p.Asp135Asn.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Damage / genetics
  • Female
  • Gene Expression Profiling
  • Genetic Predisposition to Disease / genetics
  • Genomics
  • Germ-Line Mutation
  • Humans
  • Mice
  • Mutation, Missense
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Rad51 Recombinase / metabolism
  • Radiation Tolerance / genetics
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism*


  • Poly(ADP-ribose) Polymerase Inhibitors
  • Tumor Suppressor Proteins
  • BARD1 protein, human
  • Ubiquitin-Protein Ligases
  • Rad51 Recombinase