biostudies-literatureDixon KBC Cancer Foundation Neil Macrae Hereditary Cancer Research FundProvincial Health Services Authority, British Columbia | BC Cancer AgencyCIHR602-606https://www.ebi.ac.uk/biostudies/studies/S-EPMC10172360biostudies-literatureUnknown31(5)Germline structural variants (SVs) are challenging to resolve by conventional genetic testing assays. Long-read sequencing has improved the global characterization of SVs, but its sensitivity at cancer susceptibility loci has not been reported. Nanopore long-read genome sequencing was performed for nineteen individuals with pathogenic copy number alterations in BRCA1, BRCA2, CHEK2 and PALB2 identified by prior clinical testing. Fourteen variants, which spanned single exons to whole genes and included a tandem duplication, were accurately represented. Defining the precise breakpoints of SVs in BRCA1 and CHEK2 revealed unforeseen allelic heterogeneity and informed the mechanisms underlying the formation of recurrent deletions. Integrating read-based and statistical phasing further helped defEuropean journal of human genetics : EJHGDefining the heterogeneity of unbalanced structural variation underlying breast cancer susceptibility by nanopore genome sequencing.PMC10172360NAO'Neill KBezeau MMungall AJYip SSchrader KAMoore RMungall KLFok AZhang WSharma AThibodeau MLSun SJones SJMBosdet IBilobram SShen YDixon KChan SfalseDefining the heterogeneity of unbalanced structural variation underlying breast cancer susceptibility by nanopore genome sequencing.Germline structural variants (SVs) are challenging to resolve by conventional genetic testing assays. Long-read sequencing has improved the global characterization of SVs, but its sensitivity at cancer susceptibility loci has not been reported. Nanopore long-read genome sequencing was performed for nineteen individuals with pathogenic copy number alterations in BRCA1, BRCA2, CHEK2 and PALB2 identified by prior clinical testing. Fourteen variants, which spanned single exons to whole genes and included a tandem duplication, were accurately represented. Defining the precise breakpoints of SVs in BRCA1 and CHEK2 revealed unforeseen allelic heterogeneity and informed the mechanisms underlying the formation of recurrent deletions. Integrating read-based and statistical phasing further helped def2023-01-01T00:00:00Z2023 May2025-04-26T14:32:19.842Z2025-04-06T14:35:42.673ZS-EPMC101723603679746610.1038/s41431-023-01284-1