title: Pathogenicity of DNA variants and double mutations in multiple endocrine neoplasia type 2 and von Hippel-Lindau syndrome.
abstract: BACKGROUND
  Cancer genetics is fundamental for preventive medicine, in particular in pheochromocytoma-associated syndromes. Variants in two susceptibility genes, SDHC and RET, were found in a kindred with head and neck paraganglioma. This observation of coincident DNA variants, both reported as pathogenic, in two known susceptibility genes prompted the question of their pathogenic relevance.
  
  
  OBJECTIVE
  Our objective was to elucidate the pathogenic role of the detected variants and study the prevalence of such variants.
  
  
  METHODS
  Patients were registrants from the European-American Pheochromocytoma-Paraganglioma and German von Hippel-Lindau Disease Registries.
  
  
  METHODS
  Analysis of germline mutation screening results for all pheochromocytoma-paraganglioma susceptibility genes, including RET [multiple endocrine neoplasia type 2 (MEN 2)] and VHL [von Hippel-Lindau disease (VHL)]. Cases in which more than one DNA variant was found were clinically reevaluated, and cosegregation of the disease with the variant was analyzed within the registrants' families. A total of 1000 controls were screened for the presence of detected variants, and in silico analyses were performed.
  
  
  RESULTS
  Three variants were identified, RET p.Tyr791Phe and p.Ser649Leu and VHL p.Pro81Ser. The frequencies of RET p.Ser649Leu (0.07%) and p.Tyr791Phe (0.9%) compared with controls excluded the two variants' role in the etiology of MEN 2 and VHL. None of the carriers of the RET variants who underwent prophylactic thyroidectomy showed medullary thyroid carcinoma. Clinical reinvestigation of 18 variant carriers excluded MEN 2. VHL variant p.Pro81Ser, also previously described as a mutation, did not segregate with the VHL in one family. In silico analyses for these variants predicted unmodified protein function.
  
  
  CONCLUSIONS
  RET p.Tyr791Phe and p.Ser649Leu and VHL p.Pro81Ser are definitely not pathogenic mutations for VHL and MEN 2. Misinterpretation results in irreversible clinical consequences.
authors.affiliation: Department of Nephrology, Section of Preventive Medicine, Albert-Ludwigs-University, Freiburg, D-79106 Freiburg, Germany.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Erlic
authors.forename: Michael M
authors.initials: MM
authors.lastname: Hoffmann
authors.forename: Maren
authors.initials: M
authors.lastname: Sullivan
authors.forename: Gerlind
authors.initials: G
authors.lastname: Franke
authors.forename: Mariola
authors.initials: M
authors.lastname: Peczkowska
authors.forename: Igor
authors.initials: I
authors.lastname: Harsch
authors.forename: Matthias
authors.initials: M
authors.lastname: Schott
authors.forename: Helmut E
authors.initials: HE
authors.lastname: Gabbert
authors.forename: Matti
authors.initials: M
authors.lastname: Valimäki
authors.forename: Simon F
authors.initials: SF
authors.lastname: Preuss
authors.forename: Kornelia
authors.initials: K
authors.lastname: Hasse-Lazar
authors.forename: Dariusz
authors.initials: D
authors.lastname: Waligorski
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.forename: Andrzej
authors.initials: A
authors.lastname: Januszewicz
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.forename: Hartmut P H
authors.initials: HP
authors.lastname: Neumann
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000502:physiology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D010235:Paraganglioma / Q000235:genetics; D010375:Pedigree; D010673:Pheochromocytoma / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C108096:SDHC protein, human; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human