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



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.


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.


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.


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.

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Data availability

The search terms for the literature review are included in the Methods section of the manuscript, and the studies included in the meta-analysis are listed and referenced in the supplementary material.

Change history

  • 08 July 2020

    In the original publication of the article, the first sentence in the abstract was published incorrectly.


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We thank Megan N Frone MS CGC, Mark H Greene MD, and Philip S Rosenberg PhD, for reviewing the manuscript.


This work was supported by the intramural research program of the National Cancer Institute of the National Institutes of Health, Bethesda, MD. The views presented in this article are those of the authors and should not be viewed as official opinions or positions of the National Cancer Institute, National Institutes of Health, or U.S. Department of Health and Human Services.

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BPA performed the literature review, and AFB performed the statistical analyses.

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Correspondence to Blanche P. Alter.

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Alter, B.P., Best, A.F. 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 182, 465–476 (2020).

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  • Breast cancer
  • Fanconi anemia
  • Germline pathogenic variants
  • Meta-analysis
  • Meta-regression
  • PALB2
  • BRIP1