ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1013C>T (p.Thr338Ile) (rs377767433)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570795 SCV000664515 likely benign Hereditary cancer-predisposing syndrome 2019-01-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Mendelics RCV000709106 SCV000838375 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
Invitae RCV001046577 SCV001210484 uncertain significance Multiple endocrine neoplasia, type 2 2019-11-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 338 of the RET protein (p.Thr338Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs377767433, ExAC 0.006%). This variant has been reported in an individual affected with Hirschsprung's disease (PMID: 11955539) and in both an individual affected with micromedullary thyroid carcinoma and an unaffected relative (PMID: 21810974). ClinVar contains an entry for this variant (Variation ID: 38594). Experimental studies have shown that this missense change displays low or no transforming activity behaving similar to wild type in vitro (PMID: 21810974, 25440022). In summary, this variant is a rare missense change that is not believed to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Research and Development, ARUP Laboratories RCV000032026 SCV000055358 uncertain significance not specified 2018-05-04 no assertion criteria provided literature only First report, single individual: HSCR. Second report, single family, two with mutation genotype: 1 MTC only (PMID 21810974). Third report, single individual: MTC (PMID 21054478). Additional reference: PMID 20516206. In vitro studies: PMID 21810974 and 25440022

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