p.Val804Met, the most frequent pathogenic mutation in RET, confers a very low lifetime risk of medullary thyroid cancer.

p.Val804Met, the most frequent pathogenic mutation in RET, confers a very low lifetime risk of medullary thyroid cancer.

J Clin Endocrinol Metab. 2018 Mar 23;:

Authors: Loveday C, Josephs K, Chubb D, Gunning A, Izatt L, Tischkovitz M, Ellard S, Turnbull C

Abstract
Context: To date, penetrance figures for medullary thyroid cancer (MTC) for variants in RET have been estimated from families ascertained on account of presence of MTC.
Objective: To gain estimates of penetrance unbiased by ascertainment, we analyzed 61 RET mutations assigned as disease-causing by the 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 non-TCGA ExAC, assuming lifetime penetrance for MTC of 90%, 50% and unbounded.
Setting: Population-based. Patients or other participants/Interventions. NA.
Results: 10/61 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% CI: 0.9-8%).
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: 0.9-8%), current recommendation by the American Thyroid Association of prophylactic thyroidectomy as standard for all RET mutation carriers is likely inappropriate.

PMID: 29590403 [PubMed - as supplied by publisher]

https://ift.tt/2J3hO9h