Current review of TP53 pathogenic germline variants in breast cancer patients outside Li‐Fraumeni syndrome. Issue 12 (3rd October 2018)

• Record Type: Journal Article
• Authors: Fortuno, Cristina; James, Paul A.; Spurdle, Amanda B.
• Is Part Of: Human mutation. Volume 39:Issue 12(2018)
• Page Start: 1764
• Page End: 1773
• Publication Date: 2018-10-03
• Subjects: breast cancer -- genetic testing -- germline -- multigene panels -- TP53; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23656
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Pathogenic germline variants in TP53 predispose carriers to the multi‐cancer Li‐Fraumeni syndrome (LFS). Widespread multigene panel testing is identifying TP53 pathogenic variants in breast cancer patients outside the strict clinical criteria recommended for LFS testing. We aimed to assess frequency and clinical implications of TP53 pathogenic variants in breast cancer cohorts ascertained outside LFS. Classification of TP5 3 germline variants reported in 59 breast cancer studies, and publicly available population control sets was reviewed and identified evidence for misclassification of variants. TP53 pathogenic variant frequency was determined for: breast cancer studies grouped by ascertainment characteristics; breast cancer cohorts undergoing panel testing; and population controls. Early age of breast cancer onset, regardless of family history or BRCA1/BRCA2 previous testing, had the highest pick‐up rate for TP53 carriers. Patients at risk of hereditary breast cancer unselected for features of LFS carried TP53 pathogenic variants at a frequency comparable to that of other non‐ BRCA1/2 breast cancer predisposing genes, and ∼threefold more than reported in population controls. These results have implications for the implementation of TP53 testing in broader clinical settings, and suggest urgent need to investigate cancer risks associated with TP53 pathogenic variants in individuals outside the LFS spectrum. Abstract : Early age of breast cancer onset, regardless of family history or BRCA1/2 previous testing, had the highest pick‐up rate for TP53 carriers Patients at risk of hereditary breast cancer unselected for features of LFS carried TP53 pathogenic variants at a frequency comparable to that of other non‐BRCA1/2 breast cancer predisposing genes Differences in ascertainment are likely to impact estimates of breast cancer risk due to TP53 pathogenic variants