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

dbSNP: rs79781594

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000161938	SCV000211923	pathogenic	Multiple endocrine neoplasia, type 2	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 618 of the RET protein (p.Cys618Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2A (PMID: 7915165, 9384613, 9498388, 9839497, 20979234, 22068382). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys364Ser. ClinVar contains an entry for this variant (Variation ID: 13914). 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 tolerated. Experimental studies have shown that this missense change affects RET function (PMID: 9230192). 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: 8099202, 9498388, 9839497, 20979234, 22068382, 25628771). 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.
Eurofins Ntd Llc (ga)	RCV000082050	SCV000225060	pathogenic	not provided	2017-04-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000082050	SCV000234949	pathogenic	not provided	2020-07-27	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17895320, 29433789, 29590403, 29656518, 30273935, 7915165, 8557249, 9003111, 20979234, 26254625, 26758973, 18063059, 9384613, 28647780, 28729773, 28946813, 31510104, 30911297, 29396759)
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: https://www.ncbi.nlm.nih.gov/clinvar/variation/13914/ 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	2022-09-12	criteria provided, single submitter	clinical testing	The p.C618S pathogenic mutation (also known as c.1853G>C), located in coding exon 10 of the RET gene, results from a G to C substitution at nucleotide position 1853. The cysteine at codon 618 is replaced by serine, an amino acid with dissimilar properties. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration has been identified in both sporadic and familial cases of medullary thyroid cancer (MTC) (Landsvater RM et al. Hum Genet. 1996 Jan;97(1):11-4; Elisei R et al. J. Clin. Endocrinol. Metab. 2007 Dec;92(12):4725-9; Jung J et al. J. Korean Med. Sci. 2010 Feb;25(2):226-9; Hedayati M et al. J. Thyroid Res. 2011 Jun;2011:264248; Qi XP et al. Fam. Cancer 2012 Mar;11(1):131-6). In another study, this mutation was identified in 7 unrelated families diagnosed with MEN2A. Of 14 total carriers in this study, 12 were diagnosed with medullary thyroid cancer and 2 with a pheochromocytoma. (Frank-Raue K et al. Hum. Mutat. 2011 Jan;32(1):51-8). This mutation has been classified as conferring "moderate risk" for MTC by the American Thyroid Association (Wells SA et al. Thyroid 2015 Jun; 25(6):567-610). In addition, this alteration is predicted to be deleterious by in silico analysis. Furthermore, several other pathogenic mutations have been reported at this same codon: p.C618F, p.C618G, p.C618R, and p.C618Y. Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000082050	SCV001449874	pathogenic	not provided	2017-01-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000014933	SCV004018496	pathogenic	Multiple endocrine neoplasia, type 2a	2023-04-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9230192]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7716719, 33754314, 31471357, 20979234, 22068382, 25810047].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000082050	SCV004220035	pathogenic	not provided	2020-07-10	criteria provided, single submitter	clinical testing	This variant (also known as Cys364Ser) has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant is located at one of the hotspots associated with FMTC and MEN2A, and has been reported as deleterious in multiple families/individuals with FMTC and MEN2A in the published literature (PMIDs: 7915165 (1994), 9230192 (1997), 9384613 (1998), 9839497 (1998), 25694125 (2015)). Based on the available information, this variant is classified as pathogenic.
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
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000082050	SCV001927147	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000082050	SCV001958553	pathogenic	not provided		no assertion criteria provided	clinical testing