Submissions for variant NM_020975.6(RET):c.1859G>A (p.Cys620Tyr)

dbSNP: rs77503355

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413879	SCV000490769	pathogenic	not provided	2021-07-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: transforming activity, increased phosphorylation at RET p.Tyr905 (Orgiana 2004, Ercolino 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 32408902, 31510104, 9820617, 14633923, 16158949, 15472167, 9681515, 26556299, 28698976, 8733882, 9174404, 21309721, 22865907, 21995290, 16411177, 12563086, 8103403, 9067749, 20979234, 18062802, 18248647)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000413879	SCV000886049	pathogenic	not provided	2020-12-04	criteria provided, single submitter	clinical testing	The RET c.1859G>A; p.Cys620Tyr variant is published in the medical literature in individuals affected with multiple endocrine neoplasia type 2A (MEN2A) or MEN2A-associated cancers (Donis-Keller 1993, Frank-Raue 2011, Orgiana 2004). Additionally, other amino acid substitutions at this codon (Arg, Phe, and Ser) are described as causative for MEN2A, though missense variants at this codon often exhibit incomplete penetrance (Wells 2015). The p.Cys620Tyr variant is reported as pathogenic by multiple laboratories in the ClinVar database (Variation ID: 13916), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 620 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Considering available information, the p.Cys620Tyr variant is considered to be pathogenic. References: 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. 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. Orgiana G et al. A new germline RET mutation apparently devoid of transforming activity serendipitously discovered in a patient with atrophic autoimmune thyroiditis and primary ovarian failure. J Clin Endocrinol Metab. 2004 Oct;89(10):4810-6. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610.
Invitae	RCV000021801	SCV000934750	pathogenic	Multiple endocrine neoplasia, type 2	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 620 of the RET protein (p.Cys620Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with medullary thyroid carcinoma (MTC) and pheochromocytoma (PMID: 8797874, 9820617, 16322339, 16868135, 18062802, 18063059, 20979234, 26556299). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13916). 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 tolerated. Experimental studies have shown that this missense change affects RET function (PMID: 9012462, 15472167). 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: 7849720, 7874109, 9146685, 9384613, 18206480, 19336503, 19826964, 24805091). 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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000413879	SCV001468027	pathogenic	not provided	2020-08-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408464	SCV002724071	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	clinical testing	The p.C620Y pathogenic mutation (also known as c.1859G>A), located in coding exon 10 of the RET gene, results from a G to A substitution at nucleotide position 1859. The cysteine at codon 620 is replaced by tyrosine, an amino acid with highly dissimilar properties. This pathogenic mutation has been well described in numerous individuals with familial medullary thyroid cancer (FMTC) (Donis-Keller H et al. Hum Mol Genet. 1993 Jul;2(7):851-6; Schuffenecker I et al. Hum Mol Genet. 1994 Nov;3(11):1939-43; Fink M et al. Int J Cancer. 1996 Aug 22;69(4):312-6; Frank-Raue K et al. Hum Mutat. 2011 Jan;32(1):51-8; Schrader KA et al. JAMA Oncol. 2016 Jan;2:104-11) and has also been described in a patient with Hirschsprung's disease (Frank-Raue K et al. Hum Mutat. 2011 Jan;32(1):51-8). Furthermore, codon 620 is a well-described mutation hotspot with numerous pathogenic alterations reported at this position (Kloos RT et al. Thyroid. 2009 Jun;19(6):565-612; Wells SA et al. 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. This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Athena Diagnostics Inc	RCV000413879	SCV002771205	pathogenic	not provided	2021-10-07	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Over 90% of MEN2A and FMTC families have missense variants in one of six conserved cysteine residues at codons 609, 611, 618, 620, 630 or 634 in the extracellular cysteine-rich region (PMID 19443294). This variant is defined by the American Thyroid Association as being of moderate risk for developing MTC (PMID: 19469690, 25810047). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant activates RET protein kinase transforming capability, thereby inducing the protein's oncogenic activation (PMID 9230192, 18248647, 15472167, 9012462). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease.
OMIM	RCV000014936	SCV000035192	pathogenic	Multiple endocrine neoplasia, type 2a	2013-09-04	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000014936	SCV000510547	likely pathogenic	Multiple endocrine neoplasia, type 2a	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431330	SCV000510548	likely pathogenic	Multiple endocrine neoplasia, type 2b	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441133	SCV000510549	likely pathogenic	Multiple endocrine neoplasia type 4	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420281	SCV000510550	likely pathogenic	Medullary thyroid carcinoma	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428368	SCV000510551	likely pathogenic	Multiple endocrine neoplasia, type 1	2016-05-13	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678747	SCV000804919	pathogenic	Aganglionic megacolon	2009-04-30	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000014936	SCV000804920	pathogenic	Multiple endocrine neoplasia, type 2a	2009-04-30	no assertion criteria provided	clinical testing