ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1853G>A (p.Cys618Tyr) (rs79781594)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163667 SCV000214239 pathogenic Hereditary cancer-predisposing syndrome 2017-08-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification
Invitae RCV000475953 SCV000543836 pathogenic Multiple endocrine neoplasia, type 2 2018-09-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 618 of the RET protein (p.Cys618Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (rs79781594, ExAC no frequency). This variant has been reported in several individuals affected with multiple endocrine neoplasia type 2A and familial medullary thyroid cancer (PMID: 8103403, 20516206, 21765987). It has been shown to segregate with medullary thyroid cancer in a large family (PMID: 25628771). ClinVar contains an entry for this variant (Variation ID: 24901). This variant affects a highly conserved and functionally important cysteine amino acid residue of the RET protein (PMID: 9879991, 9230192, 7824936, 9174404). Experimental studies have shown that several amino acid substitutions at this position, including p.Cys618Tyr, have transforming activity and reduced cell surface expression of RET (PMID: 9230192). Different missense substitutions at this codon (p.Cys618Arg, p.Cys618Phe, p.Cys618Ser, p.Cys618Gly) have been reported to be deleterious (PMID: 22068382, 7915165, 20979234, 9498388, 9384613, 9839497, Invitae), suggesting that this residue is critical for protein function. For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV000475953 SCV000042460 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Report of Pheo (PMID 7608256). Three family reports, 6 have the mutation genotype: 6 MTC and 1 Pheo (PMID 20979234). Youngest with MTC: 25 yr. In vitro studies: PMID 9230192. In the oldest reference, exon 10 was called exon 7. Additional references: PMID 9699127 and 11230481. Has been found with another RET change, see c.1853G>A(;)1893C>T.
Database of Curated Mutations (DoCM) RCV000423173 SCV000510467 likely pathogenic Medullary thyroid carcinoma 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429944 SCV000510468 likely pathogenic Multiple endocrine neoplasia, type 2b 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440162 SCV000510469 likely pathogenic Multiple endocrine neoplasia, type 2a 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424049 SCV000510470 likely pathogenic Multiple endocrine neoplasia, type 1 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434317 SCV000510471 likely pathogenic Multiple endocrine neoplasia, type 4 2016-05-13 no assertion criteria provided literature only

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