A Homozygous RET K666N Genotype With an MEN2A Phenotype

Abstract

Here we report a case of a homozygous RET K666N mutation leading to coincident MTC and PHEO. Heterozygous presentations of RET K666N mutations have low penetrance for isolated MTC. We believe that the gene dosage associated with the homozygosity of this variant contributed to the occurrence of bilateral PHEO.

GLOBAL ENDOCRINOLOGY: Geographical variation in the profile of RET variants in patients with medullary thyroid cancer: a comprehensive review

“…Largest series on MEN2-related RET pathogenic variants from Germany, France, Italy, United Kingdom, Brazil, Japan, and United States of America Table 1 compares the results of RET pathogenic variants causing MEN2 in the largest published series, originating from Germany (n = 533) (9,26,29,36,38,39), France (n = 437) (39,40,41), Italy (n = 237) (17,31,32,42), United Kingdom (UK) (n = 110) (43), Brazil (n = 554) (44), United States of America (USA) (n = 403) (45,46,47,48,49,50,51,52), and Japan (n = 390) (53,54,55,56,57).…”

“…As mentioned, differently from France, Germany, Italy, UK, Brazil, and Japan where the results of RET variants were consolidated by national studies, the results of RET variants from USA represent our compilation of published reports (45,46,47,48,49,50,51,52,74) (Table 1). Actually, patients from USA with MEN2 have been included in the International RET Mutation Consortium since the first studies on RET genotyping (7).…”

“…There are also interesting observations on rare variants causing MTC, such as p.Gly533Cys (74) and p.Lys666Arg (51). Another interesting paper shows 12 rare germline RET variants in a large series of 6700 cases from the Mayo Clinic and Quest Diagnostics; segregation within families suggests that p.Lys666Glu (MTC and PHEO) and Thr636insGlu-Leu-Cys-Arg; Thr636Pro, a 13bp insertion and 1bp deletion (MTC), respectively, are disease-causing variants (45).…”

Multiple endocrine neoplasia type 2 (MEN2) and RET specific modifications of the ACMG/AMP variant classification guidelines and impact on the MEN2 RET database

“…PVS1 was not used since MEN2 is generally a RET GOF disorder, and therefore null RET variants are not expected to cause MEN2 syndromes. Although there are a few reports of homozygous RET variation (Cosci et al, 2011; Elisei et al, 2004; Jaber et al, 2018; Kaldrymides et al, 2006; Lecube et al, 2002; Lesueur et al, 2005; Miyauchi et al, 2002; Silva et al, 2015) which appear to lead to a more severe phenotype in some cases, MEN2 is a dominant disorder; PM3 is for traditional recessive disorders, thus, was not used. PP2 was not used, since many missense RET variants cause HSCR only; therefore, missense RET variants are not all pathogenic for MEN2.…”