ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1853G>C (p.Cys618Ser) (rs79781594)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000161938 SCV000211923 pathogenic Multiple endocrine neoplasia, type 2 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 618 of the RET protein (p.Cys618Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals affected with medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2A (PMID: 7915165, 9498388,9839497, 9384613) and it is shown to segregate in two families with MTC (PMID: 22068382, 20979234). This variant is also known as p.Cys364Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 13914). This variant affects a highly conserved and functionally important cysteine amino acid residue of the RET protein (PMID: 9879991, 9230192, 7824936, 9174404). Experimental studies in NIH 3T3 cells demonstrated that this variant retains some transforming activity but has reduced cell surface expression (PMID: 9230192). Different missense substitutions at this codon have been reported to be deleterious (PMID: 25628771, 22068382, 20979234, 9498388, 9839497, 8099202), suggesting that this cystiene residue is critical for protein function. For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082050 SCV000225060 pathogenic not provided 2017-04-27 criteria provided, single submitter clinical testing
GeneDx RCV000082050 SCV000234949 pathogenic not provided 2018-12-28 criteria provided, single submitter clinical testing This variant is denoted RET c.1853G>C at the cDNA level, p.Cys618Ser (C618S) at the protein level, and results in the change of a Cysteine to a Serine (TGC>TCC). Using alternate nomenclature, this variant has also been published as RET Cys364Ser. This variant was observed in numerous individuals with medullary thyroid cancer and/or pheochromocytoma as well as a few individuals with Hirschsprung disease (Xue 1994, Decker 1998, Elsei 2007, Quayle 2007, Frank-Raue 2011, Aydogan BI 2016). Furthermore, this variant was shown to segregate with medullary thyroid cancer over at least four generations in a large family (Moers 1996). RET Cys618Ser was not observed in large population cohorts (Lek 2016). This variant is located within a Cysteine-rich region of the extracellular domain (Garcia-Barcelo 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000082050 SCV000605031 pathogenic not provided 2017-09-14 criteria provided, single submitter clinical testing The RET c.1853G>C; p.Cys618Ser variant (rs79781594) has been described in the literature in several families with medullary thyroid cancer (MTC) and multiple endocrine neoplasia type 2A (MEN2A) (see link, Decker 1998a, Decker 1998b, Egawa 1998, Frank-Raue 2011). Individuals with this variant show age-related penetrance for MTC and pheochromocytoma, and variants in this codon confer a high risk for developing MTC (Frank-Raue 2011). This variant is listed as pathogenic in ClinVar (Variation ID: 13914) but is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The cysteine at codon 618 is highly conserved across mammals and computational algorithms (Align GVGD, SIFT, PolyPhen2. MutationTaster) predict this variant to be damaging to the protein. Based on the above information, this variant is considered to be pathogenic. References: Link to ClinVar database for p.Cys618Ser: Decker RA et al. Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum Mol Genet. 1998 Jan;7(1):129-34. Decker RA et al. ccurrence of MEN 2a in familial Hirschsprung's disease: a new indication for genetic testing of the RET proto-oncogene. J Pediatr Surg. 1998 Feb;33(2):207-14. Egawa S et al. Genotype-phenotype correlation of patients with multiple endocrine neoplasia type 2 in Japan. Jpn J Clin Oncol. 1998 Oct;28(10):590-6. Frank-Raue K et al. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat. 2011 Jan;32(1):51-8.
Counsyl RCV000014933 SCV000677730 pathogenic Multiple endocrine neoplasia, type 2a 2017-04-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV001013348 SCV001173927 pathogenic Hereditary cancer-predisposing syndrome 2019-03-06 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification;Well-characterized mutation at same position
OMIM RCV000014933 SCV000035189 pathogenic Multiple endocrine neoplasia, type 2a 1994-04-01 no assertion criteria provided literature only
OMIM RCV000014934 SCV000035190 pathogenic Familial medullary thyroid carcinoma 1994-04-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000161938 SCV000042457 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Seven family reports, 14 have the mutation genotype: 12 MTC and 2 Pheo (PMID 20979234). Youngest with MTC: 9 yr. Patients may also have HSCR (PMID 9498388 and 9384613). In the oldest reference, codon 618 was called codon 364. Additional references: PMID 8625130, 9003111 and 15164440. Has been found with another RET change, see c.1853G>C(;)2673G>A.

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