ClinVar Genomic variation as it relates to human health

A codon 804 mutation in the RET gene leading to the substitution of valine by leucine (V804L) was first identified in 2 unrelated French families with familial medullary thyroid carcinoma (MTC; 155240) (Farndon et al., 1986; Bolino et al., 1995). Lombardo et al. (2002) studied 61 heterozygotes harboring the germline V804L mutation of the RET protooncogene in 5 independent families, including one reported by Bolino et al. (1995). A total of 31 subjects underwent surgery. Histology identified C-cell hyperplasia in 30 cases, isolated in 12 and associated with MTC in 18. Six patients with MTC had lymph node metastases. Among the 14 patients with basal detectable calcitonin (114130) level, 12 had MTC and 2 had isolated C cell hyperplasia. In most individuals carrying the V804L RET mutation, C cell disease displayed late onset and an indolent course; a pentagastrin test was negative in the majority of heterozygotes during the first 2 decades and was positive in only half of them during the third and fourth decades of life. The authors concluded that in these gene carriers, surgery may be postponed to the fourth decade of life or until the pentagastrin stimulation test becomes positive. They also suggested that their data be confirmed on a larger series of V804L carriers, but that it may offer a balanced strategy to keep under control and prevent development of the full disease phenotype. Ruiz et al. (2001), among others, had found a germline variant, ser836 to ser (S836S) (due to a nucleotide change in exon 14 of the RET gene which does not change the amino acid), that occurred at a significantly higher frequency in patients with sporadic MTC than in control subjects without sporadic MTC. Based on this observation, it had been postulated that the S836S polymorphism reacts as a low-penetrance allele in MTC and, perhaps, in FMTC families with a small number of affected members who have no typical RET gene mutations. In an extended Hungarian FMTC kindred whose members had a germline V804L mutation and a germline S836S polymorphism in separate alleles in exon 14 of the RET gene, Patocs et al. (2003) analyzed the clinical associations. The observations suggested that the coexistence of the V804L mutation and the S836S polymorphism in separate alleles did not aggravate the relatively low-risk disease phenotype characteristic in most patients with codon 804 mutations of exon 14 of the RET gene. Three of the family members who had the V804L mutation and 1 member who could not be tested for mutation were operated on for nonmetastatic MTC, while 1 member with MTC who had the V804L mutation refused surgery. In all patients affected with MTC, the disease developed relatively late in life and never caused death. Lesueur et al. (2005) compared the clinical data and age of diagnosis among 3 patients homozygous for either V804L or V804M (see 164761.0043), 6 other heterozygous cases from the same populations, and other homozygous and heterozygous subjects reported previously. The data were consistent with a model in which codon 804 mutations have low penetrance, the developing of medullary thyroid carcinoma being associated with a second germline or somatic mutation. The authors concluded that the activity and (in the case of somatic mutations) timing of these other genetic alterations in the RET gene may explain the wide clinical variability associated with germline mutations at codon 804. (less)