Pathogenicity of DNA Variants and Double Mutations in Multiple Endocrine Neoplasia Type 2 and Von Hippel-Lindau Syndrome

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2009 Nov 13

PMID 19906784

Citations 25

Authors

Zoran Erlic

Michael M Hoffmann

Maren Sullivan

Gerlind Franke

Mariola Peczkowska

Igor Harsch

Matthias Schott

Helmut E Gabbert

Matti Valimaki

Simon F Preuss

Kornelia Hasse-Lazar

Dariusz Waligorski

Mercedes Robledo

Andrzej Januszewicz

Charis Eng

Hartmut P H Neumann

Affiliations

Soon will be listed here.

Abstract

Context: 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.

Patients: Patients were registrants from the European-American Pheochromocytoma-Paraganglioma and German von Hippel-Lindau Disease Registries.

Design: 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.

Citing Articles

Results and Clinical Interpretation of Germline Analysis in a Series of Patients with Medullary Thyroid Carcinoma: The Challenge of the Variants of Uncertain Significance.

Innella G, Rossi C, Romagnoli M, Repaci A, Bianchi D, Cantarini M Cancers (Basel). 2020; 12(11).

PMID: 33167350 PMC: 7694403. DOI: 10.3390/cancers12113268.

The synergy of germline C634Y and V292M RET mutations in a northern Chinese family with multiple endocrine neoplasia type 2A.

Yang Z, Qi X, Gross N, Kou X, Bai Y, Feng Y J Cell Mol Med. 2020; 24(22):13163-13170.

PMID: 32989896 PMC: 7701567. DOI: 10.1111/jcmm.15922.

Mutational load in carotid body tumor.

Kudryavtseva A, Lukyanova E, Kalinin D, Zaretsky A, Pokrovsky A, Golovyuk A BMC Med Genomics. 2019; 12(Suppl 2):39.

PMID: 30871634 PMC: 6416835. DOI: 10.1186/s12920-019-0483-x.

Multiple Endocrine Neoplasia Syndromes from Genetic and Epigenetic Perspectives.

Khatami F, Tavangar S Biomark Insights. 2018; 13:1177271918785129.

PMID: 30013307 PMC: 6043927. DOI: 10.1177/1177271918785129.

Management of Gene Variants of Unknown Significance: Analysis Method and Risk Assessment of the Mutation p.P81S (c.241C>T).

Alosi D, Bisgaard M, Hemmingsen S, Krogh L, Mikkelsen H, Binderup M Curr Genomics. 2017; 18(1):93-103.

PMID: 28503092 PMC: 5321774. DOI: 10.2174/1389202917666160805153221.

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