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Most of compound mutations have more aggressive phenotypes than single point mutations, but the compound C634Y\/V292M variant in MTC has never been reported. Thus, we retrospectively investigated synergistic effect of C634Y and V292M <jats:italic>RET<\/jats:italic> germline mutations in family members with multiple endocrine neoplasia type 2A. Nine of 14 family members in a northern Chinese family underwent <jats:italic>RET<\/jats:italic> mutation screening using next\u2010generation sequencing and PCR followed by direct bidirectional DNA sequencing. Clinical features of nine individuals were retrospectively carefully reviewed. In vitro, the scratch\u2010wound assay was used to investigate the difference between the cells carrying different mutations. We find no patients died of MTC. All 3 carriers of the V292M variant were asymptomatic and did not have biochemical or structural evidence of disease (age: 82, 62 and 58). Among 4 C634Y mutation carriers, 2 patients had elevated calcitonin with the highest (156\u00a0pg\/mL) in an 87\u2010year\u2010old male. Two carriers of compound C634Y\/V292M trans variant had bilateral MTC with pheochromocytoma or lymph node metastasis (age: 54 and 41\u00a0years, respectively). Further, the compound C634Y\/V292M variant had a faster migration rate than either single point mutation in vitro (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.05). In conclusion, the V292M RET variant could be classified as \u2018likely benign\u2019 according to ACMG (2015). The compound variant V292M\/C634Y was associated with both more aggressive clinical phenotype and faster cell growth in vitro than was either single mutation.<\/jats:p>","DOI":"10.1111\/jcmm.15922","type":"journal-article","created":{"date-parts":[[2020,9,29]],"date-time":"2020-09-29T11:27:45Z","timestamp":1601378865000},"page":"13163-13170","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The synergy of germline C634Y and V292M <i>RET<\/i> mutations in a northern Chinese family with multiple endocrine neoplasia type 2A"],"prefix":"10.1111","volume":"24","author":[{"given":"Zheng","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University) Ministry of Education Beijing Tongren Hospital Capital Medical University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinmeng","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University) Ministry of Education Beijing Tongren Hospital Capital Medical University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neil","family":"Gross","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Surgery The University of Texas MD Anderson Cancer Center Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiujuan","family":"Kou","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University) Ministry of Education Beijing Tongren Hospital Capital Medical University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunlong","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University) Ministry of Education Beijing Tongren Hospital Capital Medical University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaru","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University) Ministry of Education Beijing Tongren Hospital Capital Medical University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bochun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University) Ministry of Education Beijing Tongren Hospital Capital Medical University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark E.","family":"Zafereo","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Surgery The University of Texas MD Anderson Cancer Center Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9505-1502","authenticated-orcid":false,"given":"Guojun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Surgery The University of Texas MD Anderson Cancer Center Houston Texas USA"},{"name":"Department of Epidemiology The University of Texas MD Anderson Cancer Center Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuanzheng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Surgery The Third Affiliated Hospital of Kunming Medical University Kunming China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huihui","family":"Li","sequence":"additional","affiliation":[{"name":"Physical Examination Center Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University) Ministry of Education Beijing Tongren Hospital Capital Medical University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhigang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University) Ministry of Education Beijing Tongren Hospital Capital Medical University Beijing 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