Submissions for variant NM_020975.6(RET):c.1859G>C (p.Cys620Ser)

dbSNP: rs77503355

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489707	SCV000576504	pathogenic	not provided	2017-05-02	criteria provided, single submitter	clinical testing	The C620S missense variant in the RET gene has been reported many times in association with multiple endocrine neoplasia type 2 (MEN2), familial medullary thyroid cancer (FMTC), and Hirschsprung disease (for examples, see Schuffenecker et al., 1994; Borrego et al., 1998; Frank-Raue et al., 2011; Igarashi et al., 2014). Of note, variants involving the Cysteine codon at position 620 have been reported to be associated with a higher incidence of pheochromocytoma and hyperparathyroidism (Yip et al., 2003). Based on currently available evidence, we consider C620S to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000489707	SCV000886050	pathogenic	not provided	2017-07-31	criteria provided, single submitter	clinical testing	The RET c.1859G>C, p.Cys620Ser variant (rs77503355) has been reported in the literature to be associated with multiple endocrine neoplasia type 2A (MEN2A), familial medullary thyroid carcinoma (FMTC) and Hirshsprung's disease (Borrego 1998, Fernandez 2003, Frank-Raue 2011, Igarashi 2014, Lore 2000, Lore 2001, Machens 2008, Romeo 1998, Wells 2015). Other missense variants at this and adjacent residues have been implicated in MEN2A, FMTC and/or Hirshsprung's disease (Wells 2015). The p.Cys620Ser variant has been listed as pathogenic in ClinVar (Variation ID: 13943), considered a variant of moderate risk (Wells 2015), and not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). Based on the above information, the variant is classified as pathogenic. References: Borrego S et al. Molecular analysis of the ret and GDNF genes in a family with multiple endocrine neoplasia type 2A and Hirschsprung disease. J Clin Endocrinol Metab. 1998; 83(9):3361-4. Fernandez R et al. The RET C620S mutation causes multiple endocrine neoplasia type 2A (MEN2A) but not Hirschsprung disease (HSCR) in a family cosegregating both phenotypes. Hum Mutat. 2003; 22(5):412-5. 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. Igarashi T et al. An extended family with familial medullary thyroid carcinoma and Hirschsprung's disease. J Nippon Med Sch. 2014; 81(2):64-9. Lore F et al. Unilateral renal agenesis in a family with medullary thyroid carcinoma. N Engl J Med. 2000; 342(16):1218-9. Lore F et al. Multiple endocrine neoplasia type 2 syndromes may be associated with renal malformations. J Intern Med. 2001; 250(1):37-42. Machens A et al. Familial prevalence and age of RET germline mutations: implications for screening. Clin Endocrinol (Oxf). 2008; 69(1):81-7. Romeo G et al. Association of multiple endocrine neoplasia type 2 and Hirschsprung disease. J Intern Med. 1998; 243(6):515-20. Wells S et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610.
Ambry Genetics	RCV001013426	SCV001174009	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-29	criteria provided, single submitter	clinical testing	The p.C620S pathogenic mutation (also known as c.1859G>C), located in coding exon 10 of the RET gene, results from a G to C substitution at nucleotide position 1859. The cysteine at codon 620 is replaced by serine, an amino acid with dissimilar properties. This alteration has been detected in multiple patients with medullary thyroid carcinoma (MTC) and segregated in a family with familial medullary thyroid carcinoma (FMTC) and Hirschsprung's disease (Schuffenecker I et al. Hum. Mol. Genet. 1994 Nov;3(11):1939-43; Igarashi T et al. J Nippon Med Sch, 2014;81:64-9; Machens A et al. Hum. Mutat., 2018 Jun;39:860-869). The American Thyroid Association provides management guidelines for individuals with mutations at codon 620 (Kloos RT et al. Thyroid. 2009 Jun;19(6):565-612). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021802	SCV001579533	pathogenic	Multiple endocrine neoplasia, type 2	2024-03-27	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 620 of the RET protein (p.Cys620Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Hirschsprung disease and/or multiple endocrine neoplasia type 2 (PMID: 10777380, 11471675, 14517954). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13943). 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: 9230192). This variant disrupts the p.Cys620 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7874109, 8909322, 16705552, 20979234, 21765987). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000489707	SCV002774397	pathogenic	not provided	2013-10-13	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). The variant is located at one of the hot spots for variants associated with FMTC and MEN2A. Additionally, the variant has been identified in individuals affected with multiple endocrine neoplasia type 2 (MEN2), and familial medullary thyroid cancer (FMTC) (PMID: 20979234) (2011), 18062802 (2008), 14517954 (2003), 10549772 (1999), 9745455 (1998), 7874109 (1994)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV004018626	SCV004930783	pathogenic	Multiple endocrine neoplasia type 2A	2024-01-05	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: 22584715, 20979234, 9681852, 24805091, 25810047].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782015	SCV005394142	pathogenic	MEN2 phenotype: Unclassified	2024-09-03	criteria provided, single submitter	clinical testing	Variant summary: RET c.1859G>C (p.Cys620Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248804 control chromosomes. c.1859G>C has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2 or Hirschsprung Disease (e.g. Schuffenecker_1994, Frank-Raue_2011, Lore_2000). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1858T>C, p.Cys620Arg), supporting the critical relevance of codon 620 to RET protein function. The following publications have been ascertained in the context of this evaluation (PMID: 20979234, 9230192, 10777380, 7874109). ClinVar contains an entry for this variant (Variation ID: 13943). Based on the evidence outlined above, the variant was classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000021802	SCV005430356	pathogenic	Multiple endocrine neoplasia, type 2	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with serine at codon 620 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 10 individuals affected with medullary thyroid carcinoma, pheochromocytoma, and/or multiple endocrine neoplasia type 2A (PMID: 10777380, 14517954, 24805091, 7874109, 10549772, 10777380, 11471675, 11454140, 14517954, 18062802, 20979234, 24805091, 28946813, 29656518, 33827484, 37529773). It has been shown that this variant segregates with medullary thyroid cancer in multiple families (PMID: 10777380, 14517954, 24805091). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.1858T>G (p.Cys620Gly), c.1858T>C (p.Cys620Arg), c.1859G>T (p.Cys620Phe), c.1859G>A (p.Cys620Tyr), and c.1860C>G (p.Cys620Trp), are well-documented pathogenic variants (ClinVar Variation ID: 24905, 13915, 13928, 13916, 13934), indicating that Cys at this position is important for RET protein function. Based on the available evidence, this variant is classified as Pathogenic.
OMIM	RCV000014970	SCV000035226	pathogenic	Familial medullary thyroid carcinoma	2001-07-01	no assertion criteria provided	literature only