Frequency of heterozygous germline pathogenic variants in genes for Fanconi anemia in patients with non-BRCA1/BRCA2 breast cancer: a meta-analysis

Breast Cancer Res Treat. 2020 Jul;182(2):465-476. doi: 10.1007/s10549-020-05710-6. Epub 2020 Jun 2.


Purpose: Germline pathogenic variants in BRCA1 (FANCD1) and BRCA2 (FANCS) do not explain all familial or sporadic cases with breast cancer. Several reports indicate a role for pathogenic variants in other genes in the Fanconi anemia/breast cancer DNA repair pathway; the strengths of these associations vary widely. Publications from 2006 through 2017 were reviewed to provide a better estimate of the role of pathogenic variants in genes in this pathway in breast cancer.

Methods: We identified cohorts and case-control reports describing heterozygous pathogenic variants in Fanconi anemia genes in breast cancer cases with high risk of a germline pathogenic variant in a non-BRCA1/2 breast cancer susceptibility gene ("familial"), and cases unselected for family history ("unselected"). Meta-analysis and meta-regression were used to estimate the frequencies of pathogenic variants in cohorts and the odds ratios (OR) in case-control studies.

Results: Meta-analysis of more than 100 reports of FANCN/PALB2 in familial breast cancer cases provided an overall pathogenic variant prevalence of 1.29% and an OR of 8.45. The prevalence in unselected cohorts was 0.64%, and the OR was 4.76. Pathogenic variants in FANCJ/BRIP1 had a prevalence of 0.5% in familial cases, and an OR of 1.62; their prevalence in unselected cases was 0.39%. FANCO/RAD51C, FANCP/SLX4, FANCU/XRCC2, FANCD2, and other FA-related genes all had prevalences of ≤ 0.5% among familial cases, and even lower in unselected cases.

Conclusions: Heterozygous pathogenic variants in FANCN/PALB2 and possibly FANCJ/BRIP1 may account for 1-2% of familial non-BRCA1/2 breast cancer cases and 0.5-1% of unselected cases. Genetic counseling and testing may be suggested for unaffected relatives.

Keywords: BRIP1; Breast cancer; Fanconi anemia; Germline pathogenic variants; Meta-analysis; Meta-regression; PALB2.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / prevention & control
  • DNA Repair / genetics
  • Fanconi Anemia Complementation Group N Protein / genetics*
  • Fanconi Anemia Complementation Group Proteins / genetics*
  • Female
  • Genetic Carrier Screening / statistics & numerical data*
  • Genetic Counseling
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Heterozygote
  • Humans
  • RNA Helicases / genetics*


  • Fanconi Anemia Complementation Group N Protein
  • Fanconi Anemia Complementation Group Proteins
  • PALB2 protein, human
  • BRIP1 protein, human
  • RNA Helicases

Supplementary concepts

  • Breast Cancer, Familial