ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1852T>G (p.Cys618Gly) (rs76262710)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000014919 SCV000053072 pathogenic Multiple endocrine neoplasia, type 2a 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Invitae RCV000228834 SCV000290534 pathogenic Multiple endocrine neoplasia, type 2 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 618 of the RET protein (p.Cys618Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in members of multiple endocrine neoplasia type 2 families affected with medullary thyroid cancer and pheochromocytoma (PMID: 8099202, 18058472, 18062802, 18063059, 20516206, 8626834), as well as in an individual with Hirschsprung’s disease (PMID: 20041006). This variant is also known as p.Cys364Gly in some of the older literature. ClinVar contains an entry for this variant (Variation ID: 13905). This variant affects a highly conserved and functionally important cysteine amino acid of the RET protein (PMID: 9879991, 9230192, 7824936, 9174404). Experimental studies have shown that several amino acid substitutions at this position including p.Cys618Gly, have transforming activity in cell culture and result in intracellular retention and reduced cell surface expression of RET (PMID: 9230192). Different missense substitutions at this codon (p.Cys618Arg, Cys618Phe, Cys618Ser) have been reported to be deleterious (PMID: 15858153, 9839497, 9498388, 20979234, 7915165, 7835899), suggesting that this residue is critical for protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000522833 SCV000616849 pathogenic not provided 2018-04-12 criteria provided, single submitter clinical testing This pathogenic variant is denoted RET c.1852T>G at the cDNA level, p.Cys618Gly (C618G) at the protein level, and results in the change of a Cysteine to a Glycine (TGC>GGC). This variant has been reported many times in association with medullary thyroid cancer and multiple endocrine neoplasia type 2 (Frank-Raue 1996, O'Keeffe 1998, Machens 2001, Haecker 2003, Paszko 2007, Romei 2010). Variants involving the Cysteine codon at position 618, including Cys618Gly, were shown to result in significantly reduced cell surface expression of RET (Ito 1997). Additionally, variants at this position have been reported to be associated with a higher incidence of pheochromocytoma (Yip 2013). RET Cys618Gly was not observed in large population cohorts (Lek 2016). This variant is located within a cysteine-rich region in 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000522833 SCV000862263 pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000522833 SCV000886048 pathogenic not provided 2017-07-07 criteria provided, single submitter clinical testing The RET c.1852T>G; p.Cys618Gly variant (rs76262710), also known in the literature as Cys364Gly, has been reported in several families with multiple endocrine neoplasia type 2A (MEN2A) and/or familial medullary thyroid carcinoma (FMTC) (Frank-Raue 2011, Heizmann 2006, Machens 2008, Mulligan 1993, Paszko 2007, Romei 2010, Quayle 2007). Functional assays show the variant to have transforming activity and results in decreased cell surface expression (Ito 1997). This variant is reported as pathogenic in ClinVar (Variation ID: 13905), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The cysteine at codon 618 is highly conserved, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Cys618Gly: https://www.ncbi.nlm.nih.gov/clinvar/variation/13905/ 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. Heizmann O et al. Presymptomatic thyroidectomy in multiple endocrine neoplasia 2a. Eur J Surg Oncol. 2006 Feb;32(1):98-102. Ito S et al. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype. Cancer Res. 1997 Jul 15;57(14):2870-2. Machens A et al. Familial prevalence and age of RET germline mutations: implications for screening. Clin Endocrinol (Oxf). 2008 Jul;69(1):81-7. Mulligan LM et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993 Jun 3;363(6428):458-60. Paszko Z et al. The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their unaffected kindred's from Central Poland. Cancer Invest. 2007 Dec;25(8):742-9. Romei C et al. Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol. 2010 Aug;163(2):301-8. Quayle FJ et al. Pheochromocytoma penetrance varies by RET mutation in MEN 2A. Surgery. 2007 Dec;142(6):800-5; discussion 805.e1.
Fulgent Genetics,Fulgent Genetics RCV000762807 SCV000893158 pathogenic Congenital central hypoventilation; Hirschsprung disease 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a 2018-10-31 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000014919 SCV000920391 pathogenic Multiple endocrine neoplasia, type 2a 2019-02-06 criteria provided, single submitter clinical testing
OMIM RCV000014919 SCV000035175 pathogenic Multiple endocrine neoplasia, type 2a 1994-01-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000228834 SCV000042459 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only Youngest with MTC: 9 yr. Youngest with Pheo: 22 yr. In vitro studies: PMID 9230192. In the oldest reference, codon 618 was called codon 364. Additional references: PMID 8640806, 16325365, 18063059 and 18062802.

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