Results of multigene panel testing in familial cancer cases without genetic cause demonstrated by single gene testing.

Dominguez-Valentin M1, Nakken S2,3, Tubeuf H4,5, Vodak D2, Ekstrøm PO2, Nissen AM6,7, Morak M6,7, Holinski-Feder E6,7, Holth A8, Capella G9, Davidson B8,10, Evans DG11,12, Martins A4, Møller P2,13, Hovig E2,14.

Author information

1: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. mev.dominguez.valentin@rr-research.no.
2: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
3: Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
4: Inserm-U1245, UNIROUEN, Normandie Univ, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.
5: Interactive Biosoftware, Rouen, France.
6: Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Ziemssenstr. 1, Munich, Germany.
7: MGZ-Medizinisch Genetisches Zentrum, Munich, Germany.
8: Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.
9: Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d'Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, L'Hospitalet de Llobregat, Barcelona, Spain, and Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
10: University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, N-, 0316, Oslo, Norway.
11: Department of Genomic Medicine, Division of Evolution and Genomic Sciences, The University of Manchester, Manchester Academic Health Science Centre, St. Mary's Hospital, Manchester, United Kingdom.
12: Prevent Breast Cancer Centre, Wythenshawe Hospital, Southmoor Road, Manchester, United Kingdom.
13: Department of Human Medicine, Universität Witten/Herdecke, Wuppertal, Germany.
14: Department of Informatics, University of Oslo, Oslo, Norway.

Abstract

We have surveyed 191 prospectively sampled familial cancer patients with no previously detected pathogenic variant in the BRCA1/2, PTEN, TP53 or DNA mismatch repair genes. In all, 138 breast cancer (BC) cases, 34 colorectal cancer (CRC) and 19 multiple early-onset cancers were included. A panel of 44 cancer-predisposing genes identified 5% (9/191) pathogenic or likely pathogenic variants and 87 variants of uncertain significance (VUS). Pathogenic or likely pathogenic variants were identified mostly in familial BC individuals (7/9) and were located in 5 genes: ATM (3), BRCA2 (1), CHEK2 (1), MSH6 (1) and MUTYH (1), followed by multiple early-onset (2/9) individuals, affecting the CHEK2 and ATM genes. Eleven of the 87 VUS were tested, and 4/11 were found to have an impact on splicing by using a minigene splicing assay. We here report for the first time the splicing anomalies using this assay for the variants ATM c.3806A > G and BUB1 c.677C > T, whereas CHEK1 c.61G > A did not result in any detectable splicing anomaly. Our study confirms the presence of pathogenic or likely pathogenic variants in genes that are not routinely tested in the context of the above-mentioned clinical phenotypes. Interestingly, more than half of the pathogenic germline variants were found in the moderately penetrant ATM and CHEK2 genes, where only truncating variants from these genes are recommended to be reported in clinical genetic testing practice.