dc.contributor.author | Loveday, C | |
dc.contributor.author | Josephs, K | |
dc.contributor.author | Chubb, D | |
dc.contributor.author | Gunning, A | |
dc.contributor.author | Izatt, L | |
dc.contributor.author | Tischkowitz, M | |
dc.contributor.author | Ellard, S | |
dc.contributor.author | Turnbull, C | |
dc.date.accessioned | 2020-09-30T14:17:58Z | |
dc.date.issued | 2018-11-01 | |
dc.identifier.citation | The Journal of clinical endocrinology and metabolism, 2018, 103 (11), pp. 4275 - 4282 | |
dc.identifier.issn | 0021-972X | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4112 | |
dc.identifier.eissn | 1945-7197 | |
dc.identifier.doi | 10.1210/jc.2017-02529 | |
dc.description.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. | |
dc.format | Print | |
dc.format.extent | 4275 - 4282 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | ENDOCRINE SOC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Carcinoma, Neuroendocrine | |
dc.subject | Multiple Endocrine Neoplasia Type 2a | |
dc.subject | Thyroid Neoplasms | |
dc.subject | Thyroidectomy | |
dc.subject | Risk Assessment | |
dc.subject | Endocrinology | |
dc.subject | Gene Frequency | |
dc.subject | Penetrance | |
dc.subject | Polymorphism, Single Nucleotide | |
dc.subject | Databases, Genetic | |
dc.subject | Adult | |
dc.subject | Aged | |
dc.subject | Middle Aged | |
dc.subject | Societies, Medical | |
dc.subject | United States | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Proto-Oncogene Proteins c-ret | |
dc.subject | Practice Guidelines as Topic | |
dc.subject | Datasets as Topic | |
dc.subject | Prophylactic Surgical Procedures | |
dc.subject | Whole Exome Sequencing | |
dc.title | p.Val804Met, the Most Frequent Pathogenic Mutation in RET, Confers a Very Low Lifetime Risk of Medullary Thyroid Cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-03-20 | |
rioxxterms.versionofrecord | 10.1210/jc.2017-02529 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2018-11 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | The Journal of clinical endocrinology and metabolism | |
pubs.issue | 11 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR | |
pubs.publication-status | Published | |
pubs.volume | 103 | |
pubs.embargo.terms | Not known | |
dc.contributor.icrauthor | Turnbull, Clare | |