p.Val804Met, the Most Frequent Pathogenic Mutation in RET, Confers a Very Low Lifetime Risk of Medullary Thyroid Cancer.
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Embargo End Date
ICR Authors
Authors
Loveday, C
Josephs, K
Chubb, D
Gunning, A
Izatt, L
Tischkowitz, M
Ellard, S
Turnbull, C
Josephs, K
Chubb, D
Gunning, A
Izatt, L
Tischkowitz, M
Ellard, S
Turnbull, C
Document Type
Journal Article
Date
2018-11-01
Date Accepted
2018-03-20
Abstract
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.
Citation
The Journal of clinical endocrinology and metabolism, 2018, 103 (11), pp. 4275 - 4282
Source Title
Publisher
ENDOCRINE SOC
ISSN
0021-972X
eISSN
1945-7197