Next generation sequencing is informing phenotype: a TP53 example

The increased availability of next generation sequencing (NGS) and multi gene panel testing has resulted in more frequent TP53 testing of families that do not meet classic testing criteria. We investigated testing criteria, family history and result outcome in a cohort of Irish probands undergoing TP53 full sequencing. All TP53 test requests processed through the national genetic testing laboratory between 2012 and 2014 were retrospectively reviewed. Personal and family cancer histories were collected, including tumour type and age at diagnosis, from two adult cancer genetic services in Ireland. Association between Li Fraumeni syndrome (LFS) or Li Fraumeni like syndrome (LFL) criteria and test result was examined. One hundred and 35 TP53 test requests were identified. Family history data and test results were available on 123 of the TP53 test requests (118 female; 5 male). 59/123 (48%) did not meet classic LFS or LFL criteria. Two individuals from this group harboured pathogenic TP53 mutations, giving a 3% mutation detection rate in those not meeting testing criteria. Both were female and had a personal history of early onset bilateral breast cancer with no reported LFS cancers in the family. 64/123 (52%) met LFS or LFL criteria and were all TP53 negative. 37/64 (57.8%) met Chompret criteria, 19/64 (29.7%) met Eeles and 7/64 (10.9%) met Eeles and Chompret and 1/64 (1.6%) met Classic LFS criteria. Stringent testing criteria miss germline mutations in TP53 . Broadening the criteria for TP53 testing may improve our understanding of the phenotype and penetrance in the association syndrome.