title: Identification of two novel mutations in the RET proto-oncogene in the same family.
abstract: BACKGROUND
  Activating germline mutations of the RET gene cause multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma (FMTC), conditions that are inherited in an autosomal dominant manner. In addition, somatic RET mutations have been identified in a variable proportion (about 30-70%) of sporadic (nonfamilial) MTC cases.
  
  
  METHODS
  We describe a Greek family with two novel likely pathogenic sequence variants of the RET gene. The first is a C to T transition at position 2458 (c.2458C>T) that causes an arginine to cysteine substitution (p.R820C) in exon 14 in the intracellular region of the kinase. This sequence variant was identified in an apparently healthy woman who had a recently deceased sister with confirmed aggressive MTC (age of onset 37 years). To assess the pathogenicity of this novel missense sequence variant, screening was performed on all available relatives: her two sons, the mother, and a second sister, including an MTC tumor sample from the deceased sister of the proband. At the time of the investigation, no clinical symptoms suggestive of multiple endocrine neoplasia type 2 or MTC were present in any of the individuals screened.
  
  
  RESULTS
  The c.2458C>T transition was found in one son, the living sister, and the mother. Interestingly, it was not present in the tumor sample from the deceased sister. Instead, an in-frame deletion of 54 nt in exon 10 resulting in a protein missing 18 amino acids from I590 to G608 (c.1766_1819del 54) was found. Both genetic alterations were present in heterozygous state.
  
  
  CONCLUSIONS
  These data suggest that the novel in-frame deletion was the disease-causing mutation in the deceased sister. The effect of the 2458C>T mutation on the activity of the kinase is under investigation.
authors.affiliation: Department of Endocrinology-Endocrine Oncology, Theagenio Cancer Hospital , Thessaloniki, Greece. kpazaitou@in.gr
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Pazaitou-Panayiotou
authors.forename: Christoforos
authors.initials: C
authors.lastname: Giatzakis
authors.forename: George
authors.initials: G
authors.lastname: Koutsodontis
authors.forename: Athanassios
authors.initials: A
authors.lastname: Vratimos
authors.forename: Alexandra
authors.initials: A
authors.lastname: Chrisoulidou
authors.forename: Themistoklis
authors.initials: T
authors.lastname: Konstantinidis
authors.forename: Smaragda
authors.initials: S
authors.lastname: Kamakari
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D018276:Carcinoma, Medullary / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D020125:Mutation, Missense; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D017384:Sequence Deletion; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret