Submissions for variant NM_020975.6(RET):c.1852T>C (p.Cys618Arg)

dbSNP: rs76262710

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000345209	SCV000225057	pathogenic	not provided	2014-07-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000345209	SCV000329488	pathogenic	not provided	2022-10-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: variant increases RET tyrosine phosphorylation activity (Chappuis-Flament et al., 1998; Okamoto et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); 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: 7849720, 7881414, 9259198, 15588376, 20516206, 27809725, 9230192, 24928018, 8675603, 24152999, 11839664, 10490816, 9745455, 9384613, 17895320, 9067749, 8626834, 20979234, 21765987, 9146685, 21325462, 21422799, 16158949, 18063059, 21054478, 15345114, 11935126, 28729773, 21575412, 26678667, 30884088, 11386462, 32948239, 29396759, 31510104, 30763276, 33340421, 14633923, 29625052, 9879991)
Invitae	RCV000021792	SCV000814259	pathogenic	Multiple endocrine neoplasia, type 2	2023-03-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 7915165, 8099202, 8103403, 8807338, 9384613, 9498388, 9839497, 20979234, 21254918, 21765987). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RET function (PMID: 7824936, 9174404, 9230192, 9879991). 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. ClinVar contains an entry for this variant (Variation ID: 13929). This missense change has been observed in individuals with multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma and Hirschsprung disease (PMID: 7849720, 7881414, 8675603, 9259198, 11935126, 14561794, 20516206, 20979234, 21422799, 21765987, 24152999, 25374962, 25628771, 25694125, 29097883). It is commonly reported in individuals of Moroccan ancestry (PMID: 7849720, 7881414, 8675603, 9259198, 11935126, 14561794, 20516206, 20979234, 21422799, 21765987, 24152999, 25374962, 25628771, 25694125, 29097883). This variant is present in population databases (rs76262710, gnomAD 0.007%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 618 of the RET protein (p.Cys618Arg).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000345209	SCV000884458	pathogenic	not provided	2018-02-11	criteria provided, single submitter	clinical testing	The RET c.1852T>C; p.Cys618Arg variant (rs76262710) has been described in the literature in individuals and families with medullary thyroid cancer (MTC) (Hedayati 2011, Peretz 1997). Individuals with this variant show age-related penetrance for MTC and pheochromocytoma and variants in this codon have the high risk of developing MTC (Frank-Raue 2011). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 13929) and is observed in the general population at a low overall frequency of 0.0004% (1/244324 alleles) in the Genome Aggregation Database. The cysteine at codon 618 is highly conserved and computational algorithms (PolyPhen2, SIFT) predict this variant to be deleterious to protein function. Based on the above information, 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; 32(1):51-8. Hedayati M et al. Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma. J Thyroid Res. 2011; Article ID 264248. Peretz H et al. Cys 618 Arg mutation in the RET proto-oncogene associated with familial medullary thyroid carcinoma and maternally transmitted Hirschsprung's disease suggesting a role for imprinting. Hum Mutat. 1997; 10(2):155-9.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000427260	SCV001366264	pathogenic	Multiple endocrine neoplasia, type 2b	2020-04-03	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3_Mod,PS4_Str,PM1,PP1_Mod,PM5_Str,PP3,PP4_Sup.
Athena Diagnostics Inc	RCV000345209	SCV001880619	pathogenic	not provided	2021-02-08	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). The American Thyroid Association has placed this variant into the ATA-MOD category, which includes the former levels A and B, for having a moderate risk of developing aggressive medullary thyroid carcinoma (MTC; see PMID: 25810047). This variant has been reported to exhibit reduced penetrance in at least one family (PMID: 9259198). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant showed transforming activity, with reduced RET surface expression (PMID: 9230192, 9879991, 30884088). Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000345209	SCV002047168	pathogenic	not provided	2021-02-08	criteria provided, single submitter	clinical testing	This variant is located at one of the hotspots associated with FMTC and MEN2A. In the published literature, the variant has been reported in multiple individuals/families with FMTC and MEN2A (PMID: 8675603 (1996), 9259198 (1997), 20979234 (2011), 21422799 (2011), 30763276 (2019)). A functional study also indicated the variant is damaging to RET protein function (PMID: 9230192 (1997)). Based on the available information, this variant is classified as pathogenic.
Sema4, Sema4	RCV002256000	SCV002529947	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-10	criteria provided, single submitter	curation
Ambry Genetics	RCV002256000	SCV002711538	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	clinical testing	The p.C618R pathogenic mutation (also known as c.1852T>C), located in coding exon 10 of the RET gene, results from a T to C substitution at nucleotide position 1852. The cysteine at codon 618 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been identified in numerous individuals fulfilling criteria for a clinical diagnosis of multiple endocrine neoplasia type 2A (MEN2A) or familial medullary thyroid cancer (FMTC) (Ambry internal data; Romei C et al. Clin. Endocrinol. (Oxf). 2011 Feb;74:241-7; Chung YJ et al. Thyroid. 2004 Oct;14:813-8; Blaugrund JE et al. Hum. Mol. Genet. 1994 Oct;3:1895-7; Frank-Raue K et al. Hum. Mutat. 2011 Jan;32:51-8; Zhao JQ et al. Hered Cancer Clin Pract. 2015 Jan;13:5). This alteration had been identified in six families in the literature presenting with a clinical diagnosis of MEN2A/FMTC and Hirschsprung disease (Hibi Y et al. Endocr. J. 2014;61:19-23; Mulligan LM et al. Hum Mol Genet. 1994 Dec;3:2163-7; Caron P et al. J Clin Endocrinol Metab.1996 Jul;81:2731-3; Peretz H et al. Hum Mutat. 1997;10:155-9; Pasini B et al. Surgery. 2002 Apr;131:373-81). It has been classified as conferring "moderate risk" for MTC by the American Thyroid Association (Wells SA. Thyroid. 2015 Jun;25:567-610). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.
Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	RCV000114391	SCV003930399	pathogenic	Multiple endocrine neoplasia, type 2a	2023-05-21	criteria provided, single submitter	clinical testing
OMIM	RCV000014954	SCV000035210	pathogenic	Familial medullary thyroid carcinoma	2014-01-01	no assertion criteria provided	literature only
OMIM	RCV000114391	SCV000148092	pathogenic	Multiple endocrine neoplasia, type 2a	2014-01-01	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442341	SCV000510452	likely pathogenic	Medullary thyroid carcinoma	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000114391	SCV000510453	likely pathogenic	Multiple endocrine neoplasia, type 2a	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434685	SCV000510454	likely pathogenic	Multiple endocrine neoplasia, type 1	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444839	SCV000510455	likely pathogenic	Multiple endocrine neoplasia type 4	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427260	SCV000510456	likely pathogenic	Multiple endocrine neoplasia, type 2b	2016-05-13	no assertion criteria provided	literature only