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dc.contributor.authorLoveday, C
dc.contributor.authorJosephs, K
dc.contributor.authorChubb, D
dc.contributor.authorGunning, A
dc.contributor.authorIzatt, L
dc.contributor.authorTischkowitz, M
dc.contributor.authorEllard, S
dc.contributor.authorTurnbull, C
dc.date.accessioned2020-09-30T14:17:58Z
dc.date.issued2018-11
dc.identifier.citationThe Journal of clinical endocrinology and metabolism, 2018, 103 (11), pp. 4275 - 4282
dc.identifier.issn0021-972X
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4112
dc.identifier.eissn1945-7197en_US
dc.identifier.doi10.1210/jc.2017-02529en_US
dc.description.abstractContext: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.formatPrint
dc.format.extent4275 - 4282
dc.languageeng
dc.language.isoeng
dc.subjectHumans
dc.subjectCarcinoma, Neuroendocrine
dc.subjectMultiple Endocrine Neoplasia Type 2a
dc.subjectThyroid Neoplasms
dc.subjectThyroidectomy
dc.subjectRisk Assessment
dc.subjectEndocrinology
dc.subjectGene Frequency
dc.subjectPenetrance
dc.subjectPolymorphism, Single Nucleotide
dc.subjectDatabases, Genetic
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectSocieties, Medical
dc.subjectUnited States
dc.subjectFemale
dc.subjectMale
dc.subjectProto-Oncogene Proteins c-ret
dc.subjectPractice Guidelines as Topic
dc.subjectDatasets as Topic
dc.subjectProphylactic Surgical Procedures
dc.subjectWhole Exome Sequencing
dc.titlep.Val804Met, the Most Frequent Pathogenic Mutation in RET, Confers a Very Low Lifetime Risk of Medullary Thyroid Cancer.
dc.typeJournal Article
dcterms.dateAccepted2018-03-20
rioxxterms.versionofrecord10.1210/jc.2017-02529
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-11en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfThe Journal of clinical endocrinology and metabolism
pubs.issue11
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR
pubs.publication-statusPublished
pubs.volume103en_US
pubs.embargo.termsNot known
dc.contributor.icrauthorTurnbull, Clareen


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