ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1859G>A (p.Cys620Tyr) (rs77503355)

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Total submissions: 13
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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 RCV000999728 SCV000886049 pathogenic none provided 2020-01-31 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 2020-10-02 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 620 of the RET protein (p.Cys620Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with medullary thyroid carcinoma (MTC) and pheochromocytoma (PMID: 20979234, 8797874, 18063059, 16322339, 18062802, 9820617, 16868135, 26556299) and has been observed to segregate with MTC in affected families (PMID: 20979234). ClinVar contains an entry for this variant (Variation ID: 13916). Experimental studies have shown that this missense change leads to constitutive dimerization and activation of the RET receptor tyrosine kinase (PMID: 15472167, 9012462). This variant disrupts the p.Cys620 amino acid residue in RET. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 7849720, 19826964, 18206480, 9384613, 24805091, 19336503, 9146685, 7874109), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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
OMIM RCV000014936 SCV000035192 pathogenic Multiple endocrine neoplasia, type 2a 2013-09-04 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000021801 SCV000042467 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Youngest with MTC: 18 yr. In vitro studies: PMID 9230192. In the oldest reference, exon 10 was called exon 7. Additional references: PMID 9820617, 20979234, 18063059, 16868135 and 8797874.
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 Hirschsprung disease 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

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