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Concurrent Pathogenic Variants of BRCA1, MUTYH and CHEK2 in a Hereditary Cancer Family

  • Nihat Bugra Agaoglu
    Affiliations
    Department of Medical Genetics, Division of Cancer Genetics, Umraniye Training and Research Hospital, Istanbul, Turkey

    Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States
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  • Ozden Hatirnaz Ng
    Affiliations
    Department of Medical Biology, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey

    Department of Medical Genetics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey

    Acibadem University Rare Diseases and Orphan Drugs Application and Research Center, Istanbul, Turkey
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  • Busra Unal
    Affiliations
    Department of Medical Genetics, Division of Cancer Genetics, Umraniye Training and Research Hospital, Istanbul, Turkey
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  • Ozlem Akgun Dogan
    Affiliations
    Department of Medical Genetics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey

    Department of Pediatrics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
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  • Ufuk Amanvermez
    Affiliations
    Department of Genome Studies, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
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  • Jale Yildiz
    Affiliations
    Department of Medical Genetics, Division of Cancer Genetics, Umraniye Training and Research Hospital, Istanbul, Turkey
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  • Levent Doganay
    Affiliations
    Department of Gastroenterology and Hepatology, Umraniye Training and Research Hospital, Umraniye, Istanbul, Turkey
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  • Author Footnotes
    1 co-senior/last authors
    Arezou A. Ghazani
    Footnotes
    1 co-senior/last authors
    Affiliations
    Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, United States

    Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States

    Harvard Medical School, Boston, MA, United States
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  • Author Footnotes
    1 co-senior/last authors
    Huma Q. Rana
    Correspondence
    Corresponding author at: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, United States.
    Footnotes
    1 co-senior/last authors
    Affiliations
    Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States

    Harvard Medical School, Boston, MA, United States

    Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, United States
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  • Author Footnotes
    1 co-senior/last authors
    2 Co-corresponding authors

      Highlights

      • Concurrent variations are rarely found in hereditary cancers.
      • In a breast cancer patient, a monoallelic BRCA1 and biallelic MUTYH variations, and in her uncle concurrent monoallelic CHEK2 and monoallelic MUTYH variations were detected.
      • Nine additional individuals were also positive for concurrent variations and there were breast, colon, prostate, and brain cancer cases running in the family.
      • Concurrent variations need a special attention in the management of cases with positive family history.

      Abstract

      Concurrent pathogenic variants (PVs) in cancer predisposition genes have been reported in 0.1–2% of hereditary cancer (HC) patients. Determining concurrent PVs is crucial for the diagnosis, treatment, and risk assessment of unaffected family members. Next generation sequencing based diagnostic tests, which are widely used in HCs, enable the evaluation of multiple genes in parallel. We have screened the family members of a patient with bilateral breast cancer who was found to have concurrent PVs in BRCA1 (NM_007294.3;c.5102_5103del, p.Leu1701Glnfs*14) and MUTYH (NM_001128425.1;c.884C>T, p.Pro295Leu). Further analysis revealed concurrent PVs in CHEK2 (NM_007194.4;c.1427C>T, p.Thr476Met) and MUTYH (NM_001128425.1;c.884C>T, p.Pro295Leu) in the maternal uncle of the index case. Eight additional family members were found to have PVs in BRCA1 and MUTYH among 26 tested relatives. The sister and the brother of the index case who were diagnosed with breast and colon cancers, respectively, presented with the same genotype as the index case. Each family member was evaluated individually for clinical care and surveillance. This is the first report describing a family with BRCA1, MUTYH and CHEK2 concurrent PVs. Our findings provide valuable information for the assessment and management considerations for families with concurrent PVs.

      Keywords

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