Submissions for variant NM_020975.6(RET):c.1858T>C (p.Cys620Arg)

dbSNP: rs77316810

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182580	SCV000234932	pathogenic	not provided	2022-12-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: auto-kinase and phoshorylation activities, increased proliferation activity, impaired protein maturation, decreased cell surface expression, mouse model demonstrating tumorigenesis and intestinal hypoganglionosis (Ito 1997, Chappuis-Flament 1998, Arighi 2004, Carniti 2006, Yin 2007); 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: 9384613, 9067749, 9230192, 7835899, 18209889, 19853744, 17514199, 17623957, 21986619, 23744765, 30763276, 16158949, 20979234, 29020875, 12711285, 33340421, 7633441, 16565500, 19336503, 18206480, 15355438, 21765987, 18062802, 20152359, 7881414, 22584707, 20516206, 9681852, 7874109, 25694125, 9090527, 9824583, 17021738, 22584721, 25810047, 7915165, 17372903, 18063059, 8909322, 17316110, 14715928, 9879991, 22897442, 31510104, 31447099, 32179705, 33178136, 30787465, 34987852, 17188172, 11955539, 30349395, 27207748, 11564857, 27847096, 19469690, 8918855, 33754314, 17102091, 15744028, 10790203, 14633923)
Invitae	RCV000232285	SCV000290535	pathogenic	Multiple endocrine neoplasia, type 2	2023-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 620 of the RET protein (p.Cys620Arg). 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 / medullary thyroid carcinoma (PMID: 7874109, 7881414, 9090527, 9681852, 10790203, 19336503, 21765987, 21986619). This variant is also known as the "Janus mutation". ClinVar contains an entry for this variant (Variation ID: 13915). 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, 9879991, 14715928). 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: 9230192, 9879991, 14715928). 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.
Ambry Genetics	RCV000568259	SCV000664463	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-19	criteria provided, single submitter	clinical testing	The p.C620R pathogenic mutation (also known as c.1858T>C), located in coding exon 10 of the RET gene, results from a T to C substitution at nucleotide position 1858. The cysteine at codon 620 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been described in multiple families with RET-associated phenotypes including multiple endocrine neoplasia type 2A (MEN2A), familial medullary thyroid cancer (FMTC), and Hirschsprung disease (HSCR) (Schuffenecker I et al. Hum. Mol. Genet. 1994 Nov;3(11):1939-43; Pelet A et al. J. Med. Genet. 2005 Mar;42(3):e18; Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun;94(6):1938-44; Hedayati M et al. J Thyroid Res 2011; 264248; Vaclavikova E et al. Pediatr. Surg. Int. 2012 Feb;28(2):123-8). This mutation is located at codon 620, a well-described mutation hotspot site, and has been categorized by the American Thyroid Association as having moderate risk for MTC (formerly category B) and is associated with a pheochromocytoma risk of 13%–24% (Wells et al. Thyroid. 2015;25(6):567-610). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000182580	SCV000886055	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	The RET c.1858T>C, p.Cys620Arg variant (rs77316810) is reported in the literature in multiple individuals affected with multiple endocrine neoplasia type 2A (MEN2A) and/or familial medullary thyroid carcinoma (FMTC) (Donis-Keller 1993, Boedeker 2009, Hedayati 2011, Vaclavikova 2012). This variant is also reported in ClinVar (Variation ID: 13915). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.897). Based on the above information, the variant is classified as pathogenic. References: Boedeker CC et al. Head and neck paragangliomas in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2009 Jun;94(6):1938-44. PMID: 19336503. Donis-Keller H et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993 Jul;2(7):851-6. PMID: 8103403. 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. 2011:264248. PMID: 21765987. Vaclavikova E et al. Hirschsprung's disease and medullary thyroid carcinoma: 15-year experience with molecular genetic screening of the RET proto-oncogene. Pediatr Surg Int. 2012 Feb;28(2):123-8. PMID: 21986619.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826204	SCV000967762	pathogenic	Multiple endocrine neoplasia, type 2; Aganglionic megacolon	2018-01-03	criteria provided, single submitter	clinical testing	The p.Cys620Arg variant in RET has been reported in over 30 individuals with cli nical features of multiple endocrine neoplasia type 2A (MEN2A; Mathiesen 2017, C huang 2016, Heilman 2016, Yeganeh 2015, Virtanen 2013, Frank-Raue 2011, Moore 20 09, Fialkowski 2008, Hofstra 2000, Schuffenecker 1994) and was absent from large population databases. The variant segregated with the disease in >50 affected r elatives (Mathiesen 2017, Vaclavikova 2012, Moore 2009, Fialkowski 2008, Hofstra 2000, Romeo 1998, Mulligan 1994). Multiple individuals with this variant were a lso determined to have Hirschsprung disease. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID#13915). In vitro functi onal studies provide some evidence that the p.Cys620Arg variant may impact prote in function (Arighi 2004, Chappuis-Flament 1998, Ito 1997). Mouse animal models have shown that this variant causes pre-cancerous lesions in the adrenal gland a nd C-cell hyperplasia in aged mice in heterozygotes, and kidney agenesis and int estinal aganglionosis in homozygotes (Yin 2007, Carniti 2006). In summary, this variant meets criteria to be classified as pathogenic for MEN2A in an autosomal dominant manner based upon segregation studies, absence from controls, and funct ional evidence. This variant is also associated with a risk of developing Hirsch sprung disease. Pathogenic variants in exon 10 of RET, especially affecting codo ns 618 and 620, often cause both MEN 2A and Hirschsprung disease (Eng 1996, Amer ican Thyroid Association Guidelines Task Force 2009). ACMG/AMP Criteria applied (Richards 2015): PS4, PP1_Strong, PM2, PM5, PS3_Moderate, PP3.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000182580	SCV001449927	pathogenic	not provided	2018-05-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000232285	SCV002050817	pathogenic	Multiple endocrine neoplasia, type 2	2021-12-07	criteria provided, single submitter	clinical testing	Variant summary: RET c.1858T>C (p.Cys620Arg) 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 248804 control chromosomes (gnomAD). c.1858T>C has been reported in the literature in multiple individuals and families affected with Multiple Endocrine Neoplasia Type 2, Familial Medullary Thyroid Carcinoma and Hirschsprung Disease (e.g. Mulligan_1994, Hedayati_2011, Mathiesen_2017). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that C620R-expressing cells are unable to migrate, differentiate, and be protected from apoptosis in response to GDNF but they possess ligand-independent rapid proliferation activity, providing an explanation for the ability of the variant to lead to both gain- and loss-of-function RET-associated diseases (Mograbi_2001, Arighi_2004). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000182580	SCV002550387	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	RCV000014935	SCV003930400	pathogenic	Multiple endocrine neoplasia type 2A	2023-05-21	criteria provided, single submitter	clinical testing
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV003324711	SCV004030449	pathogenic	Hirschsprung disease, susceptibility to, 1	2023-08-29	criteria provided, single submitter	clinical testing
OMIM	RCV000014935	SCV000035191	pathogenic	Multiple endocrine neoplasia type 2A	2013-09-04	no assertion criteria provided	literature only
Human Genomics Unit, Institute for molecular medicine Finland (FIMM)	RCV000736276	SCV000864573	likely pathogenic	Aganglionic megacolon	2013-01-01	no assertion criteria provided	research