Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer

Seth K. Rummel, Leann Lovejoy, Craig D. Shriver, Rachel E. Ellsworth*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Purpose: Although breast cancer in young women accounts for <10% of diagnoses annually, tumors in young patients exhibit more aggressive characteristics and higher mortality rates. Determination of the frequency of germline mutations in cancer predisposition genes is needed to improve the understanding of breast cancer etiology in young women. Methods: All female patients enrolled in the Clinical Breast Cancer Project between 2001 and 2015 and diagnosed with invasive breast cancer before age 40 were included in this study. Family history was classified using the NCCN Familial Risk Assessment guidelines. Targeted sequencing of 94 cancer predisposition genes was performed using peripheral blood DNA. Variants were detected using VariantStudio and classified using ClinVar. Results: Seven percent (141/1980) of patients were young women and 44 had a significant family history. Sequencing was completed for 118 women with genomic DNA. Pathogenic mutations were present in 27 patients: BRCA1 (n = 10), BRCA2 (n = 12), TP53 (n = 1), and CHEK2 (n = 4). Mutations classified as pathogenic were also detected in APC (n = 1) and MUTYH (n = 2). Variants of uncertain significance (VUS) were detected in an additional 17 patients in ten genes. Discussion: Pathogenic mutations in high- and moderate-risk breast cancer genes were detected in 23% of young women with an additional 3% having pathogenic mutations in colon cancer predisposition genes. VUS were observed in 14% of women in genes such as ATM, BRCA2, CDH1, CHEK2, and PALB2. Identification of those non-genetic factors is critical to reduce the burden of breast cancer in this population.

Original languageEnglish
Pages (from-to)593-601
Number of pages9
JournalBreast Cancer Research and Treatment
Issue number3
StatePublished - 1 Aug 2017
Externally publishedYes


  • Breast cancer
  • Genetic predisposition
  • Pathogenic mutations
  • Young women


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