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

dbSNP: rs76262710

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000014919	SCV000053072	pathogenic	Multiple endocrine neoplasia type 2A	2022-04-06	criteria provided, single submitter	clinical testing	Variant summary: RET c.1852T>G (p.Cys618Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249114 control chromosomes. c.1852T>G has been widely reported in the literature in multiple individuals and families affected with Familial Medullary Carcinoma od the Thyroid (FMTC) and features of Multiple Endocrine Neoplasia Type 2A (MEN2A) (example, Frank-Raue_1996, Machens_2001, Okeefe_1998, Mulligan_1993). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating an increased ability to transform NIH-3T3 cells in-vitro (example, Ito_1997). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228834	SCV000290534	pathogenic	Multiple endocrine neoplasia, type 2	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 618 of the RET protein (p.Cys618Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with medullary thyroid cancer and pheochromocytoma and Hirschsprung’s disease (PMID: 8099202, 8626834, 18058472, 18062802, 18063059, 20041006, 20516206). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys364Gly in some of the older literature. ClinVar contains an entry for this variant (Variation ID: 13905). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RET function (PMID: 7824936, 9174404, 9230192, 9879991). This variant disrupts the p.Cys618 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7835899, 7915165, 9498388, 9839497, 15858153, 20979234). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000522833	SCV000616849	pathogenic	not provided	2023-10-30	criteria provided, single submitter	clinical testing	Reported in at least one patient with MEN2A and Hirschsprung's disease (PMID: 20041006); Published functional studies demonstrate significantly reduced cell surface expression of RET (PMID: 9230192); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9067749, 31043326, 32125936, 31364476, 33603219, 30050099, 20979234, 12686527, 8626834, 9146685, 11238493, 16411177, 7835899, 8099202, 7907913, 9868860, 3078962, 18063059, 18058472, 12721726, 21422799, 27349013, 20516206, 18062802, 29396759, 16325365, 29656518, 14633923, 33827484, 24064755, 20301434, 9230192, 20041006)
Eurofins Ntd Llc (ga)	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	2019-12-08	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 by multiple laboratories 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: 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, susceptibility to, 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
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000522833	SCV001449786	pathogenic	not provided	2014-10-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408462	SCV002717145	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-09	criteria provided, single submitter	clinical testing	The p.C618G pathogenic mutation (also known as c.1852T>G), located in coding exon 10 of the RET gene, results from a T to G substitution at nucleotide position 1852. The cysteine at codon 618 is replaced by glycine, an amino acid with highly dissimilar properties. This mutation is located in the RET extracellular domain and has been associated with both MEN2A and FMTC phenotypes (Mulligan LM et al. Nature. 1993;363(6428): 458-60; Paszko Z et al. Cancer Invest. 2007;25(8):742-49; Machens A & Dralle H. Clin. Endocrinol. (Oxf) 2008 Jul;69(1):81-7; Frank-Raue K et al. Hum Mutat. 2011;32(1):51-58). Of note, this mutation is also designated as p.C364G in published literature. Several other alterations at this codon, including p.C618R, p.C618S, and p.C618F, have also been described as pathogenic. The American Thyroid Association Guidelines Task Force has provided recommendations for individuals with RET gene mutations (Wells SA et al. Thyroid. 2015 Jun; 25(6):567-610). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470710	SCV002769371	pathogenic	Familial medullary thyroid carcinoma	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with Hirschsprung disease (MIM#142623) and medullary thyroid carcinoma (MTC) (MIM#155240), respectively (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Carriers of this variant may or may not develop MTC, it is regarded as high risk for disease onset (PMID: 29656518, OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity, however these variants are more likely to cause Hirschsprung’s disease (OMIM). 0200 - Variant is predicted to result in a missense amino acid change from cysteine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 – Two alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Decipher). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple alternative missense changes at codon 618 are reported as pathogenic (ClinVar), and it is described as the most commonly mutated residue in patients with familial MTC (PMID: 29656518). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in many individuals with multiple endocrine neoplasia or MTC (ClinVar, PMID: 29656518, PMID: 18058472). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Myriad Genetics, Inc.	RCV000014919	SCV004043880	pathogenic	Multiple endocrine neoplasia type 2A	2023-05-10	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 29656518, 20979234, 33827484, 18063059, 18058472, 24064755, 25810047]. Functional studies indicate this variant impacts protein function [PMID: 9230192].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000522833	SCV004220034	pathogenic	not provided	2013-11-04	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with medullary thyroid cancer and pheochromocytoma (PMIDs: 8099202 (1993), 18058472 (2007), 18062802 (2008), 20516206 (2010), 24794695 (2014), 27207748 (2016), as well as in an individual with Hirschsprung's disease (PMID: 20041006 (2009)). A functional study found reduced cell surface expression (PMID: 9230192 (1997)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV004760333	SCV005373957	pathogenic	Hirschsprung disease, susceptibility to, 1	2024-09-22	criteria provided, single submitter	clinical testing
OMIM	RCV000014919	SCV000035175	pathogenic	Multiple endocrine neoplasia type 2A	1994-01-01	no assertion criteria provided	literature only