Submissions for variant NM_020975.6(RET):c.1859G>T (p.Cys620Phe)

dbSNP: rs77503355

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000233944	SCV000290536	pathogenic	Multiple endocrine neoplasia, type 2	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 620 of the RET protein (p.Cys620Phe). 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 (PMID: 7915165, 8909322, 16705552, 19443294, 20979234). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13928). 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. 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, 9012462, 9230192, 9879991, 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.
Eurofins Ntd Llc (ga)	RCV000485714	SCV000342003	pathogenic	not provided	2016-05-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000411165	SCV000489831	pathogenic	MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB	2016-05-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000014953	SCV000489832	pathogenic	MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA	2016-05-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000485714	SCV000565489	pathogenic	not provided	2022-12-27	criteria provided, single submitter	clinical testing	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: 8909322, 19443294, 33340421, 19826964, 14715928, 16705552, 20979234, 21765987, 7916559, 25694125, 7874109, 18976013, 25810047, 26033033, 31510104, 20516206, 14633923, 18063059, 20664475, 7915165, 19469690, Khalfa2021[abstract])
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001382	SCV001158582	pathogenic	not specified	2018-11-05	criteria provided, single submitter	clinical testing	The RET c.1859G>T; p.Cys620Phe variant has been described in the literature in individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (FMTC) (American Thyroid Association Guidelines Task Force 2009, Hedayati 2011, Romei 2011, Wells 1994). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13928), but it is absent from general population-based databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 620 is highly conserved across species, it occurs in the cysteine-rich extracellular RET domain and computational programs (PolyPhen2, SIFT) predict this variant to be deleterious. Additionally, other amino acid substitutions at this codon (Ser, Arg, Gly, Trp, and Tyr) have been reported in individuals with MEN2 and FMTC and are considered pathogenic (American Thyroid Association Guidelines Task Force 2009, Frank-Raue 2011, Romei 2011). Based on available evidence, the p.Cys620Phe variant is considered to be pathogenic. References: American Thyroid Association Guidelines Task Force et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19(6):565-612. 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;2011:264248. 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. Romei C et al. RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC). Clin Endocrinol (Oxf). 2011 Feb;74(2):241-7. Wells SA Jr et al. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg. 1994 Sep;220(3):237-4.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000485714	SCV001449873	pathogenic	not provided	2017-01-13	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000485714	SCV002522514	pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002255999	SCV002529948	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-14	criteria provided, single submitter	curation
Ambry Genetics	RCV002255999	SCV002722193	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-10	criteria provided, single submitter	clinical testing	The p.C620F pathogenic mutation (also known as c.1859G>T), located in coding exon 10 of the RET gene, results from a G to T substitution at nucleotide position 1859. The cysteine at codon 620 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple families who satisfy diagnostic criteria for multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid cancer (FMTC) (Schuffenecker I et al. Hum Molec Genet. 1994;3(11):1939-1943, Hedayati M et al. J Thyroid Res. 2011;2011:264248, Frank-Raue K et al. Hum Mutat. 2011 Jan;32(1):51-8), Vaclavikova E, Endocrine 2009 Dec; 36(3):419-24, Dvorakova S, Exp. Clin. Endocrinol. Diabetes 2006 Apr; 114(4):192-6). This mutation is located in codon 620 of the RET gene, a well-described mutation hotspot, and has been categorized by the American Thyroid Association as having moderate risk for MTC and is associated with a pheochromocytoma incidence rate of 13%–24% (Wells, et al. Thyroid. 2015;25(6):567-610). Based on the available evidence, p.C620F is classified as a pathogenic mutation.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000485714	SCV004027571	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
OMIM	RCV000014953	SCV000035209	pathogenic	MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA	1994-04-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000485714	SCV001928988	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000485714	SCV001958437	pathogenic	not provided		no assertion criteria provided	clinical testing