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The aim of this study is to screen and identify high\u2010penetrate genes for FNMTC. A total of 34 families with more than two first\u2010degree relatives diagnosed as papillary thyroid cancer without other familial syndrome were recruited. Whole exome and target gene sequencing were performed for candidate variants. These variants were screened and analyzed with ESP6500, ExAC, 1000 genomes project, and the Cancer Genome Atlas (TCGA) with SIFT score and Polyphen2 prediction. Finally, we identified recurrent genetic mutation of <jats:italic>MAP2K5<\/jats:italic> variants c.G961A and c.T1100C (p. A321T and p.M367 T) as susceptibility loci for FNMTC. The frequencies of <jats:italic>MAP2K5<\/jats:italic> c.G961A and c.T1100C were found, 0.0385 and 0.0259 in FNMTC and 0 and 0.00022523 in healthy Chinese controls (n = 2200, P &lt; 0.001), respectively. Both variants were located in the protein kinase domain. The functional study showed that MAP2K5 A321T or M367 T could consistently phosphorylate downstream protein ERK5 on site Ser731 + Thr733 or Ser496, promoting nuclear translocation and subsequently altering target gene expressions. Our data revealed that MAP2K5 variants A321T or M367 T can activate MAP2K5\u2013ERK5 pathway, alter downstream gene expression, and subsequently induce thyroid epithelial cell malignant transformation. While classic MAP2K1\/2(MEK1\/2)\u2013ERK1\/2 signaling is well known for driving sporadic NMTC, our research indicated that MAP2K5 (MEK5) is a susceptibility gene for FNMTC. These findings highlight the potential application of <jats:italic>MAP2K5<\/jats:italic> for molecular diagnosis as well as early prevention.<\/jats:p>","DOI":"10.1002\/ijc.31825","type":"journal-article","created":{"date-parts":[[2018,8,22]],"date-time":"2018-08-22T16:39:53Z","timestamp":1534955993000},"page":"1321-1330","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Whole exome and target sequencing identifies MAP2K5 as novel susceptibility gene for familial non\u2010medullary thyroid carcinoma"],"prefix":"10.1002","volume":"144","author":[{"given":"Feng","family":"Ye","sequence":"first","affiliation":[{"name":"Laboratory of Pathology West China Hospital, Sichuan University  Chengdu China"},{"name":"Key Laboratory of Transplant Engineering and Immunology Ministry of Health, West China. 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