ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1859G>T (p.Cys620Phe) (rs77503355)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233944 SCV000290536 pathogenic Multiple endocrine neoplasia, type 2 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 620 of the RET protein (p.Cys620Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC, no frequency). This sequence change has been reported in members of multiple endocrine neoplasia type 2A families affected with medullary thyroid cancer and pheochromocytoma with strong evidence of disease co-segregation (PMID: 8909322, 16705552, 19443294, 20979234, 7915165). This variant has been referred to as p.Cys366Phe in the literature. ClinVar contains an entry for this variant (Variation ID: 13928). This substitution affects a highly conserved and functionally important amino acid (PMID: 9879991, 9230192). Different nucleotide changes resulting in several different amino acid changes at the p.Cys620 residue have been previously reported as pathogenic (PMID: 7874109, 9012462, 20979234). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000485714 SCV000342003 pathogenic not provided 2016-05-09 criteria provided, single submitter clinical testing
Counsyl RCV000411165 SCV000489831 pathogenic Multiple endocrine neoplasia, type 2b 2016-05-08 criteria provided, single submitter clinical testing
Counsyl RCV000014953 SCV000489832 pathogenic Multiple endocrine neoplasia, type 2a 2016-05-08 criteria provided, single submitter clinical testing
GeneDx RCV000485714 SCV000565489 pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing The C620F missense variant in the RET gene has been reported many times in association with multiple endocrine neoplasia type 2 (MEN2), and medullary thyroid cancer (for examples, see Schuffenecker et al., 1994; Hedayati et al., 2011; Yeganeh et al., 2015). This substitution occurs at a position that is conserved across species, and in silico analysis predicted this variant is probably damaging to the protein structure/function. 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 C620F to be pathogenic.
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.
OMIM RCV000014953 SCV000035209 pathogenic Multiple endocrine neoplasia, type 2a 1994-04-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000233944 SCV000055362 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Three family reports, 8 have the mutation genotype: 3 MTC and 2 Pheo (PMID 20979234). Youngest with MTC: 27 yr. Additional references: PMID 8909322, 18976013, 19443294, 18063059 and 7874109. Has been found with another RET change, see c.[1859G>T;2372A>T].

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