Exome sequencing identifies RASSF1 and KLK3 germline variants in an Iranian multiple-case breast cancer family.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101247089 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-0849 (Electronic) Linking ISSN: 17697212 NLM ISO Abbreviation: Eur J Med Genet Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam : Elsevier, c2005-
    • Subject Terms:
      Breast Neoplasms*/genetics ; Exome*; Female ; Genetic Predisposition to Disease ; Germ Cells ; Humans ; Iran ; Kallikreins ; Pedigree ; Prostate-Specific Antigen ; Tumor Suppressor Proteins/genetics
    • Abstract:
      Breast cancer is the most frequent malignancy among women in both developed and developing countries. Although several genes have been identified to harbor germline variants contributing to breast cancer risk, much of the heritability for breast cancer is yet undefined. In the present study, we have performed exome sequencing to detect susceptibility genes in an Iranian family with five first-degree family members affected with breast cancer. We identified novel candidate variants with predicted pathogenicity in RASSF1, KLK3 and FAM81B. The RASSF1 and KLK3 variants, but not the FAM81B variant, partially co-segregated with disease in the investigated pedigree and were not found in additional screenings outside the specific family. RASSF1 p.S135F is a missense substitution abolishing the ATM phosphorylation site, and KLK3 variant p.M1? is a deletion at the initiation codon that is predicted to abolish translation to the functional kallikrein protease, PSA. Our study suggests germline variation in RASSF1 and KLK3 as potential candidate contributors to familial breast cancer predisposition and illustrates the difficulties to determine the causal genetic risk factor among novel variants restricted to a single family.
      (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
    • Contributed Indexing:
      Keywords: Breast cancer risk; Cyclin D1; Exome sequencing; Genetic susceptibility; Segregation analysis
    • Accession Number:
      0 (RASSF1 protein, human)
      0 (Tumor Suppressor Proteins)
      EC 3.4.21.- (KLK3 protein, human)
      EC 3.4.21.- (Kallikreins)
      EC 3.4.21.77 (Prostate-Specific Antigen)
    • Publication Date:
      Date Created: 20220115 Date Completed: 20220404 Latest Revision: 20220531
    • Publication Date:
      20221213
    • Accession Number:
      10.1016/j.ejmg.2022.104425
    • Accession Number:
      35032689