ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1902C>G (p.Cys634Trp) (rs77709286)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000405235 SCV000886051 pathogenic not provided 2018-03-14 criteria provided, single submitter clinical testing The RET c.1902C>G; p.Cys634Trp variant (rs77709286), along with several other variants at this position (Cys634Arg/Gly/Ser/Tyr), have been described in individuals and families affected with multiple endocrine neoplasia type IIA (MEN2A), familial medullary thyroid carcinoma (FMTC), and pheochromocytoma (Hedayati 2011, Hofstra 1996, Mulligan 1994, Neumann 2002, Punales 2003). Further, variants at this position are considered high risk for MTC and high penetrance of pheochromocytoma (Wells 2015). The p.Cys634Trp variant has been reported as pathogenic by several laboratories in ClinVar (Variation ID: 13918) and is only observed in 1 out of 242460 alleles in the Genome Aggregation Database. The cysteine at codon 634 is highly conserved and computational algorithms (SIFT, PolyPhen2) predict this variant to be deleterious. Further, functional studies demonstrate that this variant causes the RET protein to be constitutively activated (Santoro 1995). Based on available information, this variant is considered pathogenic. References: 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. Hofstra R et al. RET mutation screening in familial cutaneous lichen amyloidosis and in skin amyloidosis associated with multiple endocrine neoplasia. J Invest Dermatol. 1996; 107(2):215-8. Mulligan L et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet. 1994; 6(1):70-4. Neumann HP et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002 346(19):1459-66. Punales MK et al. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003; 88(6): 2644-9. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995 Jan 20;267(5196):381-3. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610.
Database of Curated Mutations (DoCM) RCV000432112 SCV000504812 likely pathogenic Neoplasm of the thyroid gland 2014-12-26 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442512 SCV000504813 likely pathogenic Medullary thyroid carcinoma 2016-03-10 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444799 SCV000510458 likely pathogenic Multiple endocrine neoplasia, type 1 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424817 SCV000510459 likely pathogenic Multiple endocrine neoplasia, type 2b 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000014939 SCV000510460 likely pathogenic Multiple endocrine neoplasia, type 2a 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417418 SCV000510461 likely pathogenic Multiple endocrine neoplasia, type 4 2016-05-13 no assertion criteria provided literature only
GeneDx RCV000405235 SCV000329489 pathogenic not provided 2018-09-07 criteria provided, single submitter clinical testing This pathogenic variant is denoted RET c.1902C>G at the cDNA level, p.Cys634Trp (C634W) at the protein level, and results in the change of a Cysteine to a Tryptophan (TGC>TGG). This variant has been observed in several individuals with medullary thyroid carcinoma (MTC) and/or pheochromocytoma, and has been found to segregate with disease in multiple MEN2A kindreds (Lips 1994, Punales 2003, Hedayati 2006, Paun 2013, Lang 2015, Pandit 2016). Variants at codon Cysteine 634 occur in ~85% of families with MEN2A (Mulligan 1994, Mulligan 1995). On functional interrogation, RET Cys634Trp displayed high transforming efficiency and clonogenic ability, and led to constitutive activation of the RET protein (Santoro 1995). RET Cys634Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Cysteine-rich domain (Garcia-Barcelo 2004). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. We consider this variant to be pathogenic.
Invitae RCV000459040 SCV000543831 pathogenic Multiple endocrine neoplasia, type 2 2018-03-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 634 of the RET protein (p.Cys634Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals and families affected with MEN2A with evidence of segregation (PMID: 11939755, 24331334). ClinVar contains an entry for this variant (Variation ID: 13918). In addition, codon 634 mutations (p.Cys634Arg, p.Cys634Tyr, p.Cys634Ser, p.Cys634Phe) of the RET gene are highly prevalent (>80%) in patients affected with MEN2A (PMID: 7907913, 12000816). Two of these missense changes (p.Cys634Tyr, p.Cys634Phe) have previously been determined to be pathogenic (Invitae database). This suggests that the cysteine residue is critical for RET protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this variant disrupts RET protein function in vitro (PMID: 7824936). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014939 SCV000035195 pathogenic Multiple endocrine neoplasia, type 2a 2007-09-27 no assertion criteria provided literature only
OMIM RCV000014940 SCV000035196 pathogenic Pheochromocytoma 2007-09-27 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000459040 SCV000042493 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Youngest with MTC: 3 yr. Youngest with Pheo: 18 yr (PMID 17898100, 23404858). Youngest with HPT 5 yr (PMID 27406704). In vitro studies: PMID 8570194. Additional references: PMID 18794325, 11939755, 7915822, and 12788868. Has been found with another RET change, see c.1902C>G(;)1903C>G and c.[1902C>G];[1946C>T ].

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