ClinVar Miner

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

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000405235 SCV000329489 pathogenic not provided 2021-08-18 criteria provided, single submitter clinical testing 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); Published functional studies demonstrate a damaging effect: high transforming efficiency and clonogenic ability, constitutive activation of RET protein (Santoro 1995); Not observed at a significant frequency in large population cohorts (Lek 2016); 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: 7824936, 14633923, 33450337, 29625052, 20516206, 30763276, 22226210, 31510104, 31263477, 28186607, 7915822, 8557249, 12788868, 23416954, 24331334, 21765987, 17623957, 20979234, 18794325, 16507829, 18322301, 25795775, 15588376, 26071011, 12000816, 28469506, 7907913, 20672905, 27539324, 11939755, 32235612, 33071967, 33125973)
Invitae RCV000459040 SCV000543831 pathogenic Multiple endocrine neoplasia, type 2 2020-05-13 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.
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.
Ambry Genetics RCV001013621 SCV001174230 pathogenic Hereditary cancer-predisposing syndrome 2017-06-13 criteria provided, single submitter clinical testing The p.C634W pathogenic mutation (also known as c.1902C>G), located in coding exon 11 of the RET gene, results from a C to G substitution at nucleotide position 1902. The cysteine at codon 634 is replaced by tryptophan, an amino acid with highly dissimilar properties. Codon 634 in the RET gene is a well known hot spot for pathogenic mutations, and individuals with mutations in this codon have a high risk for MEN2A related manifestations. The American Thyroid Association recommends that individuals with mutation in codon 634 begin surveillance, screening, and/or possible surgical interventions in early childhood (American Thyroid Association Guidelines Task Force. Thyroid 2009 Jun;19(6):565-612; Wells SA Jr et al. <span style="font-size:12px"><span style="color:rgb(0, 0, 0); font-family:arial,helvetica,clean,sans-serif">Thyroid. 2015 Jun;25(6):567-610). This pathogenic mutation has been reported in several unrelated families diagnosed with MEN2A (Mulligan LM et al. Nat. Genet. 1994 Jan; 6(1):70-4; Hedayati M et al. J Thyroid Res 2011;264248; Păun DL et al. Chirurgia (Bucur) 2013;108(6):900-3). This pathogenic mutation has also been reported in two unrelated individuals with nonsyndromic pheochromocytomas but no other relevant family history (Neumann HP et al. N. Engl. J. Med. 2002 May; 346(19):1459-66). The p.C634W mutation has also been detected in a 23 year old female diagnosed with a unilateral pheochromocytoma as well as medullary thyroid cancer (Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23). Based on the available evidence, p.C634W is classified as a pathogenic mutation.
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 ].
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

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