ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1852T>C (p.Cys618Arg) (rs76262710)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000345209 SCV000225057 pathogenic not provided 2014-07-07 criteria provided, single submitter clinical testing
GeneDx RCV000345209 SCV000329488 pathogenic not provided 2016-05-06 criteria provided, single submitter clinical testing The C618R missense variant in the RET gene has been reported previously in association with RET-related disorders (for examples, see Mulligan et al., 1994; Peretz et al., 1997; Hibi et al., 2014). The C618R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C618R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Missense variants in the same residue (C618S, C618G, C618F, C618Y) have been reported in the Human Gene Mutation Database in association with RET-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider C618R to be pathogenic.
Invitae RCV000021792 SCV000814259 pathogenic Multiple endocrine neoplasia, type 2 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 618 of the RET protein (p.Cys618Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs76262710, ExAC 0.01%). This variant has been reported in numerous individuals and families affected with multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma and Hirschsprung disease (PMID: 21422799, 11935126, 24152999, 9259198, 8675603, 20979234, 7849720, 21765987, 25628771, 25694125, 20516206, 29097883, 25374962, 14561794, 7881414), and was reported to segregate with disease in several families (PMID: 11935126, 25628771, 24152999, 9259198, 8675603, 7881414, 20979234). In addition, this variant has been suggested as a founder mutation in the Cypriot, of Moroccan Jewish origin (PMID: 21422799, 9259198). ClinVar contains an entry for this variant (Variation ID: 13929). This variant affects a highly conserved and functionally important cysteine amino acid of the RET protein (PMID: 9879991, 9230192, 7824936, 9174404). Experimental studies have shown that several amino acid substitutions at this position, including p.Cys618Arg, have transforming activity in vitro and result in intracellular retention and reduced cell surface expression (PMID: 9230192). Different missense substitutions at this codon (p.Cys618Ser, p.Cys618Gly, p.Cys618Phe, p.Cys618Tyr) have been determined to be pathogenic (PMID: 7915165, 9498388,9839497, 9384613, 20979234, 8099202, 8807338, 21765987, 21254918, 8103403). This suggests that the cysteine residue is critical for RET protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000345209 SCV000884458 pathogenic not provided 2018-02-11 criteria provided, single submitter clinical testing The RET c.1852T>C; p.Cys618Arg variant (rs76262710) has been described in the literature in individuals and families with medullary thyroid cancer (MTC) (Hedayati 2011, Peretz 1997). Individuals with this variant show age-related penetrance for MTC and pheochromocytoma and variants in this codon have the high risk of developing MTC (Frank-Raue 2011). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 13929) and is observed in the general population at a low overall frequency of 0.0004% (1/244324 alleles) in the Genome Aggregation Database. The cysteine at codon 618 is highly conserved and computational algorithms (PolyPhen2, SIFT) predict this variant to be deleterious to protein function. Based on the above information, this variant is considered pathogenic. References: 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; 32(1):51-8. 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; Article ID 264248. Peretz H et al. Cys 618 Arg mutation in the RET proto-oncogene associated with familial medullary thyroid carcinoma and maternally transmitted Hirschsprung's disease suggesting a role for imprinting. Hum Mutat. 1997; 10(2):155-9.
OMIM RCV000014954 SCV000035210 pathogenic Familial medullary thyroid carcinoma 2014-01-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000021792 SCV000042458 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Youngest with MTC: 8 yr. Youngest with Pheo: 19 yr. Patients may also have HSCR, which occurs in ~33% of p.C618R families (PMID 7881414, 8675603 and 9259198). In vitro studies: RET activation (PMID 9879991 and 9230192). In the oldest reference, exon 10 was called exon 7. Additional references: PMID 17895320, 18063059 and 11935126.
OMIM RCV000114391 SCV000148092 pathogenic Multiple endocrine neoplasia, type 2a 2014-01-01 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442341 SCV000510452 likely pathogenic Medullary thyroid carcinoma 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000114391 SCV000510453 likely pathogenic Multiple endocrine neoplasia, type 2a 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434685 SCV000510454 likely pathogenic Multiple endocrine neoplasia, type 1 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444839 SCV000510455 likely pathogenic Multiple endocrine neoplasia, type 4 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427260 SCV000510456 likely pathogenic Multiple endocrine neoplasia, type 2b 2016-05-13 no assertion criteria provided literature only

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