Variable population prevalence estimates of germline TP53 variants: A gnomAD‐based analysis

Reports of variable cancer penetrance in Li–Fraumeni syndrome (LFS) have raised questions regarding the prevalence of pathogenic germline TP53 variants. We previously reported higher‐than‐expected population prevalence estimates in sequencing databases composed of individuals unselected for cancer history. This study aimed to expand and further evaluate the prevalence of pathogenic and likely pathogenic germline TP53 variants in the gnomAD dataset (version r2.0.2, n = 138,632). Variants were selected and classified based on our previously published algorithm and compared with alternative estimates based on three different classification databases: ClinVar, HGMD, and the UMD_TP53 database. Conservative prevalence estimates of pathogenic and likely pathogenic TP53 variants were within the range of one carrier in 3,555–5,476 individuals. Less stringent classification increased the approximate prevalence to one carrier in every 400–865 individuals, mainly due to the inclusion of the controvertible p.N235S, p.V31I, and p.R290H variants. This study shows a higher‐than‐expected population prevalence of pathogenic and likely pathogenic germline TP53 variants even with the most conservative estimates. However, these estimates may not necessarily reflect the prevalence of the classical LFS phenotype, which is based upon family history of cancer. Comprehensive approaches are needed to better understand the interplay of germline TP53 variant classification, prevalence estimates, cancer penetrance, and LFS‐associated phenotype.

[1]  R. Gelman,et al.  Differences in TP53 Mutation Carrier Phenotypes Emerge From Panel-Based Testing , 2018, Journal of the National Cancer Institute.

[2]  Amalio Telenti,et al.  Identification of misclassified ClinVar variants using disease population prevalence , 2016, bioRxiv.

[3]  S. Macklin,et al.  Observed frequency and challenges of variant reclassification in a hereditary cancer clinic , 2017, Genetics in Medicine.

[4]  Pierre Hainaut,et al.  Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li–Fraumeni syndrome , 2018, Current opinion in oncology.

[5]  E. Karlins,et al.  Higher‐than‐expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history , 2017, Human mutation.

[6]  C. Gau,et al.  Somatic TP53 variants frequently confound germline testing results , 2017, Genetics in Medicine.

[7]  Keith Nykamp,et al.  Sources of discordance among germ-line variant classifications in ClinVar , 2017, Genetics in Medicine.

[8]  David Malkin,et al.  Inherited TP53 Mutations and the Li-Fraumeni Syndrome. , 2017, Cold Spring Harbor perspectives in medicine.

[9]  T. Frebourg,et al.  Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage , 2017, Human molecular genetics.

[10]  Soma Das,et al.  Clinical Laboratories Collaborate to Resolve Differences in Variant Interpretations Submitted to ClinVar , 2017, Genetics in Medicine.

[11]  S. Manley,et al.  Detection of somatic variants in peripheral blood lymphocytes using a next generation sequencing multigene pan cancer panel. , 2017, Cancer genetics.

[12]  G. Zambetti,et al.  The Inherited p53 Mutation in the Brazilian Population. , 2016, Cold Spring Harbor perspectives in medicine.

[13]  P. Rosenberg,et al.  Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li‐Fraumeni syndrome cohort , 2016, Cancer.

[14]  Trevor Hastie,et al.  REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. , 2016, American journal of human genetics.

[15]  Dmitriy Sonkin,et al.  TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data , 2016, Human mutation.

[16]  C. Ki,et al.  Germline TP53 Mutation and Clinical Characteristics of Korean Patients With Li-Fraumeni Syndrome , 2016, Annals of laboratory medicine.

[17]  Matthew S. Lebo,et al.  Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium. , 2016, American journal of human genetics.

[18]  P. Hainaut,et al.  Rare germline variant (rs78378222) in the TP53 3' UTR: Evidence for a new mechanism of cancer predisposition in Li-Fraumeni syndrome. , 2016, Cancer genetics.

[19]  E. Harkness,et al.  The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes , 2016, Human mutation.

[20]  Ricardo Villamarín-Salomón,et al.  ClinVar: public archive of interpretations of clinically relevant variants , 2015, Nucleic Acids Res..

[21]  James Y. Zou.  Analysis of protein-coding genetic variation in 60,706 humans , 2015, Nature.

[22]  Matthew S. Lebo,et al.  Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium. , 2016, American journal of human genetics.

[23]  C. Bonaïti‐pellié,et al.  Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  Heidi L Rehm,et al.  ClinGen--the Clinical Genome Resource. , 2015, The New England journal of medicine.

[25]  S. Mccarroll,et al.  Clonal hematopoiesis and blood-cancer risk. , 2015, The New England journal of medicine.

[26]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[27]  S. Gabriel,et al.  Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. , 2014, The New England journal of medicine.

[28]  T. Soussi,et al.  TP53 Mutations in Human Cancer: Database Reassessment and Prospects for the Next Decade , 2014, Human mutation.

[29]  Tze Hau Lam,et al.  Mapping the p53 transcriptome universe using p53 natural polymorphs , 2013, Cell Death and Differentiation.

[30]  Emily H Turner,et al.  Actionable, pathogenic incidental findings in 1,000 participants' exomes. , 2013, American journal of human genetics.

[31]  P. Stenson,et al.  The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine , 2013, Human Genetics.

[32]  Thierry Soussi,et al.  The TP53 website: an integrative resource centre for the TP53 mutation database and TP53 mutant analysis , 2012, Nucleic Acids Res..

[33]  William Wheeler,et al.  Detectable clonal mosaicism and its relationship to aging and cancer , 2012, Nature Genetics.

[34]  Jean Louis Fournier,et al.  The TP 53 website : an integrative resource centre for the TP 53 mutation database and TP 53 mutant analysis , 2012 .

[35]  Magali Olivier,et al.  TP53 mutations in human cancers: origins, consequences, and clinical use. , 2010, Cold Spring Harbor perspectives in biology.

[36]  S. Sommer,et al.  Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  A. Mes-Masson,et al.  Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families , 2008, Breast Cancer Research and Treatment.

[38]  H. Sugimura,et al.  Identification and characterization of a novel germ line p53 mutation in familial gastric cancer in the Japanese population. , 2007, Carcinogenesis.

[39]  H. Meijers-Heijboer,et al.  Two TP53 germline mutations in a classical Li-Fraumeni syndrome family , 2007, Familial Cancer.

[40]  S. Kato,et al.  Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations , 2005, Human mutation.

[41]  J. M. Boutell,et al.  Functional protein microarrays for parallel characterisation of p53 mutants , 2004, Proteomics.

[42]  S. Kato,et al.  Understanding the function–structure and function–mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[43]  P. Pharoah,et al.  Prediction of pathogenic mutations in patients with early-onset breast cancer by family history , 2003, The Lancet.

[44]  J. Varley,et al.  Characterization of germline TP53 splicing mutations and their genetic and functional analysis , 2001, Oncogene.

[45]  C. Portwine,et al.  p53 compound heterozygosity in a severely affected child with Li-Fraumeni Syndrome , 1999, Oncogene.