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

Abstract

ContextTo 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.ObjectiveTo 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.DesignFor 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.SettingPopulation-based.ResultsTen 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%].ConclusionsBased 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.

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“…Furthermore, penetrance may vary substantially between alleles in the same gene . For example, population‐based studies indicate that the p.Val804Met RET variant confers a much lower lifetime risk of medullary thyroid cancer (MTC) than other MEN2A‐associated RET mutations . For variants with reduced penetrance, the additional genetic and/or environmental factors contributing to disease expression remain to be defined.…”

“…In addition, although estimates of disease penetrance are frequently reported at the gene level, different pathogenic variants in the same gene may be associated with marked differences in penetrance. For example, although the majority of MEN2A‐associated RET mutations are reported to have a high disease penetrance (eg 70%‐100% by the age of 70 years), recent population‐level studies predict that the Val804Met variant has a much lower penetrance of 1%‐8% (dashed box) . In addition, distinguishing low penetrance disease alleles from benign variants is challenging and typically requires large disease and control cohorts to establish genuine associations.…”

“…RET variant confers a much lower lifetime risk of medullary thyroid cancer (MTC) than other MEN2A-associated RET mutations. 23,24 For variants with reduced penetrance, the additional genetic and/or environmental factors contributing to disease expression remain to be defined. Disease expressivity refers to the range of disease phenotypes observed between individuals harbouring the same variant.…”

“…As such, the penetrance estimates above are intended to be illustrative. References relevant to specific genes include AIP 19,42 ; CDC73 123,124 ; MEN1 26,125 ; SDH complex genes 11,12,120,121 ; PRKAR1A 28 ; RET 23,24,126 ; and VHL. 127 Penetrance estimates for MEN4 due to CDKN1B mutations are not available due to low numbers of reported cases.…”

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“…It is highly likely that the population penetrance and phenotype differ from this. For example, unbiased population estimates of penetrance for medullary thyroid cancer of p.Val804Met mutations in the RET oncogene were far lower than estimated in carrier-based analysis [26]. Conversely, the penetrance of PALB2 mutations for breast cancer is far greater than initially estimated [1••, 27].…”