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CancerGenetics

• Beyond BRCA1/2: Germline Pathogenic Variants in Fanconi Anemia Pathway Genes Identified Through Whole-Exome Reanalysis in Early-Onset Breast Cancer

• Sara Jamali,¹ Mirsalar Kahaei,² Toktam Dehghani,³ Majid Mojarrad,^4,* Seyed Mehdi Kalantar,⁵
  1. Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences
  2. Faculty of Medicine, Department of Medical Genetics, Mashhad University of Medical Sciences
  3. Department of Medical Informatics, Faculty of Medicine, Mashhad University of Medical Sciences
  4. Faculty of Medicine, Department of Medical Genetics, Mashhad University of Medical Sciences
  5. Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
  
  
  
• Introduction: Whole-exome sequencing (WES) has expanded hereditary cancer evaluation beyond established breast cancer susceptibility genes, yet the clinical interpretation of pathogenic variants in less well-characterized DNA-repair genes remains challenging. The Fanconi anemia (FA)/BRCA pathway is a conserved DNA-repair network involved in the resolution of DNA interstrand crosslinks and maintenance of genomic stability. Biallelic pathogenic variants in several FA genes cause Fanconi anemia, whereas heterozygous pathogenic variants in selected pathway genes, including BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO, are established or clinically relevant cancer susceptibility findings. In contrast, the contribution of heterozygous variants in other FA genes to breast cancer risk remains incompletely defined. This distinction is particularly important because pathogenicity of an individual variant does not, by itself, establish that the corresponding gene is a clinically actionable breast cancer susceptibility gene. Reanalysis of previously generated exome data provides an opportunity to incorporate updated gene–disease knowledge, variant classifications, and pathway-level biological insights that may not have been available during the initial analysis. Here, we characterize two germline pathogenic variants in FA pathway genes identified through WES reanalysis of women with early-onset or clinically significant breast cancer and examine their relevance to the expanding landscape of DNA-repair genes in hereditary cancer evaluation.
• Methods: Previously generated germline WES data from two unrelated women with breast cancer were systematically reanalyzed in two stages. First, variants in established breast cancer susceptibility genes recommended by the National Comprehensive Cancer Network (NCCN) were evaluated. Following negative findings in these genes, the analysis was expanded to a broader breast cancer-associated gene list compiled from established cancer genomics resources and published literature. Variants were prioritized based on sequencing quality, population frequency, predicted molecular consequence, available clinical evidence, and ACMG/AMP criteria. Variant classifications were assessed using Franklin, GeneBe, VarSome, and ClinVar. Clinical phenotype and family history were subsequently reviewed to evaluate the potential relevance of identified variants.
• Results: Case 1 was a 32-year-old woman with early-onset breast cancer carried a heterozygous FANCA variant, NM_000135.4:c.2T>C (p.Met1?), classified as Pathogenic. Her family history included colorectal cancer in a maternal uncle at age 53 and prostate cancer in her maternal grandfather at age 81. The variant affects the canonical translation-initiation codon and has been reported as pathogenic in the context of Fanconi anemia and showed a balanced allelic representation (allele balance 0.53), supporting a high-confidence heterozygous germline call. Case 2 was A 37-year-old woman with metastatic breast cancer and bone involvement carried a heterozygous FANCE nonsense variant, NM_021922:c.355C>T (p.Gln119Ter), classified as Pathogenic and supported by strong loss-of-function evidence (PVS1 Strong).The variant was supported by an allele balance of approximately 0.41, compatible with a heterozygous germline variant. FANCA and FANCE both participate in the FA core complex, linking the two findings through a common DNA-repair pathway despite their different clinical presentations.
• Conclusion: These cases demonstrate the potential of WES reanalysis to uncover high-confidence germline pathogenic variants in DNA-repair genes beyond the canonical BRCA1/2 framework. Importantly, the findings also illustrate a central interpretive challenge in hereditary cancer genomics: variant pathogenicity and gene-level cancer susceptibility are related but distinct concepts. A pathogenic FANCA or FANCE variant establishes that the variant itself has disease-associated molecular consequences in an appropriate genetic context. However, it does not automatically establish that heterozygosity in the respective gene confers a breast cancer risk comparable to established susceptibility genes. Therefore, these findings should be interpreted in conjunction with gene-specific penetrance data, phenotype, family history, and the strength of available gene–disease evidence rather than being used alone to guide risk-reduction management. The identification of two pathogenic variants within the same DNA-repair pathway nevertheless highlights the value of pathway-informed reanalysis and supports continued investigation of non-canonical FA genes in hereditary breast cancer cohorts. More broadly, systematic reanalysis of archived WES data can increase the clinical yield of previously generated genomic datasets as variant knowledge and gene–disease relationships evolve.
• Keywords: Early-onset breast cancer; Whole-exome sequencing reanalysis; Fanconi anemia pathway; FANCA; FANCE;