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p.Val804Met, the Most Frequent Pathogenic Mutation in RET, Confers a Very Low Lifetime Risk of Medullary Thyroid Cancer.

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Loveday, Chey 
Josephs, Katherine 
Chubb, Daniel 
Gunning, Adam 
Izatt, Louise 


CONTEXT: To date, penetrance figures for medullary thyroid cancer (MTC) for variants in rearranged during transfection (RET) have been estimated from families ascertained because of the presence of MTC. OBJECTIVE: To gain estimates of penetrance, unbiased by ascertainment, we analyzed 61 RET mutations assigned as disease causing by the American Thyroid Association (ATA) in population whole-exome sequencing data. DESIGN: For the 61 RET mutations, we used analyses of the observed allele frequencies in ∼51,000 individuals from the Exome Aggregation Consortium (ExAC) database that were not contributed via The Cancer Genome Atlas (TCGA; non-TCGA ExAC), assuming lifetime penetrance for MTC of 90%, 50%, and unbounded. SETTING: Population-based. RESULTS: Ten of 61 ATA disease-causing RET mutations were present in the non-TCGA ExAC population with observed frequency consistent with penetrance for MTC of >90%. For p.Val804Met, the lifetime penetrance for MTC, estimated from the allele frequency observed, was 4% [95% confidence interval (CI), 0.9% to 8%]. CONCLUSIONS: Based on penetrance analysis in carrier relatives of p.Val804Met-positive cases of MTC, p.Val804Met is currently understood to have high-lifetime penetrance for MTC (87% by age 70), albeit of later onset of MTC than other RET mutations. Given our unbiased estimate of penetrance for RET p.Val804Met of 4% (95% CI, 0.9% to 8%), the current recommendation by the ATA of prophylactic thyroidectomy as standard for all RET mutation carriers is likely inappropriate.



Adult, Aged, Carcinoma, Neuroendocrine, Databases, Genetic, Datasets as Topic, Endocrinology, Female, Gene Frequency, Humans, Male, Middle Aged, Multiple Endocrine Neoplasia Type 2a, Penetrance, Polymorphism, Single Nucleotide, Practice Guidelines as Topic, Prophylactic Surgical Procedures, Proto-Oncogene Proteins c-ret, Risk Assessment, Societies, Medical, Thyroid Neoplasms, Thyroidectomy, United States, Exome Sequencing

Journal Title

J Clin Endocrinol Metab

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The Endocrine Society