ClinVar Genomic variation as it relates to human health

The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)

This variant, formerly titled COWDEN SYNDROME 3, with the Included titles of Intestinal Carcinoid Tumors, Paragangliomas-1, Pheochromocytoma, and Somatic Merkel Cell Carcinoma, has been reclassified based on a review of the ExAC database by Hamosh (2018): the G12S variant was present in 881 of 121,216 alleles and in 5 homozygotes, with an allele frequency of 0.007268 (July 11, 2018). Cowden Syndrome In 4 unrelated patients with a Cowden-like phenotype (see 158350), Ni et al. (2008) identified a heterozygous G12S substitution in the SDHD gene. This mutation was not identified in 700 control subjects. The G12S mutation was associated with increased manganese superoxide dismutase expression, increased reactive oxygen species, and a 1.9-fold increase in both AKT and MAPK expression. All 4 patients were women, ranging in age from 42 to 69 years. Three of 4 manifested breast cancer; 1 had thyroid cancer; 1 had renal cancer; 1 had uterine cancer; and 3 had uterine leiomyomas. Bayley (2011) commented that the findings of Ni et al. (2008) require independent confirmation, and suggested that functional studies of the SDH variants are essential before recommendations can be made for appropriate genetic counseling. Pheochromocytoma/Paraganglioma Syndrome 1 In a patient with an extraadrenal intraabdominal pheochromocytoma (PPGL1; 168000), Gimm et al. (2000) identified a gly12-to-ser (G12S) substitution in the SDHD gene. There was involvement of the jugular fossa, suggesting malignancy, An unrelated patient with an intestinal lipoma had the same mutation. The G12S substitution was identified in 1.3% of control chromosomes, and the authors concluded that it is either a low-penetrance mutation or a rare polymorphism. In a patient with a caudal equina paraganglioma and cerebellar tumors that had developed 22 years later, Masuoka et al. (2001) identified the G12S substitution. There was no family history of paragangliomas. Twenty-one additional cases of spinal paraganglioma had the wildtype SDHD sequence. Cascon et al. (2002) identified the G12S and S68S substitutions in a patient with sporadic pheochromocytoma. However, the G12S substitution was identified in 5 (2.5%) of 200 control chromosomes, and Cascon et al. (2002) concluded that G12S is a polymorphism. In addition, the S68S substitution was found in all 5 controls with the G12S substitution, indicating that the 2 substitutions are in linkage disequilibrium. In a patient with paragangliomas, Perren et al. (2002) identified a heterozygous G12S substitution. Clinical manifestations included a paratracheal paraganglioma, C-cell hyperplasia of the thyroid, and hyperplasia of ACTH-producing cells of the pituitary. There was no family history of the disorder, and the mutation was not identified in 93 controls. Intestinal Carcinoid Tumors and Merkel Cell Carcinoma Kytola et al. (2002) identified a 34G-A transition in exon 1 of the SDHD gene, resulting in the G12S substitution, in the primary tumor of a man diagnosed with nonfamilial midgut carcinoid (see 114900) at 71 years of age. The alteration was also present in the constitutional tissue of the patient, confirming its germline origin. Because the G12S variant led to the elimination of a restriction site for BanI, a restriction cleavage assay was applied to confirm the presence of the change in the patient and to exclude its occurrence in 200 normal individuals. The patient also carried a normally occurring silent polymorphism, ser68-to-ser (S68S), which was previously reported by Baysal et al. (2000). The same G12S missense change accompanied by the S68S polymorphism was also observed by Kytola et al. (2002) in a Merkel cell carcinoma tumor. No normal DNA was available to clarify whether the sequence variants occurred somatically or were present in the germline. To determine whether the tumors with G12S/S68S were associated with a common founder haplotype, Kytola et al. (2002) genotyped 4 microsatellites close to and flanking SDHD. The results excluded the existence of a common founder chromosome. The tumor in the patient with midgut carcinoid showed loss of heterozygosity on genotyping with markers D11S5011 and D11S1986. (less)