ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1900T>C (p.Cys634Arg) (rs75076352)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3DMed Clinical Laboratory Inc RCV000677899 SCV000804061 pathogenic Thyroid carcinoma 2017-10-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000082051 SCV000605036 pathogenic not provided 2017-08-14 criteria provided, single submitter clinical testing The RET c.1900T>C; p.Cys634Arg variant is a common pathogenic variant identified in families with multiple endocrine neoplasia type 2A, and segregating with affected individuals (Hofstra 1996, Mulligan 1994, Wells 2015). Functional characterization of the variant protein indicates increased auto-phosphorylation, and activation of downstream targets (Pasini 1997, Santoro 1995). This results in enhanced malignant transformation of cells expressing the variant protein (Cosci 2011, Pasini 1997, Santoro 1995). The variant is listed in the dbSNP variant database (rs75076352) and observed in the Exome Aggregation Consortium general population database at a frequency of 0.00083 percent. The cysteine at residue 634 is highly conserved, and computational algorithms (Align GVGD, Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic. References: Cosci B et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer. 2011; 18(5):603-12. 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. Pasini A et al. Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain. Oncogene. 1997; 15(4):393-402. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995; 267(5196):381-3. Wells S et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610.
Ambry Genetics RCV000163338 SCV000213872 pathogenic Hereditary cancer-predisposing syndrome 2017-09-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position
Athena Diagnostics Inc RCV000082051 SCV000842751 pathogenic not provided 2018-05-04 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000014937 SCV000804921 pathogenic Multiple endocrine neoplasia, type 2a 2014-08-22 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000420995 SCV000504811 likely pathogenic Medullary thyroid carcinoma 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420446 SCV000510487 likely pathogenic Multiple endocrine neoplasia, type 4 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430685 SCV000510488 likely pathogenic Multiple endocrine neoplasia, type 1 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000014937 SCV000510489 likely pathogenic Multiple endocrine neoplasia, type 2a 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431794 SCV000510491 likely pathogenic Multiple endocrine neoplasia, type 2b 2016-05-13 no assertion criteria provided literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082051 SCV000225405 pathogenic not provided 2013-01-22 criteria provided, single submitter clinical testing
GeneDx RCV000082051 SCV000234951 pathogenic not provided 2018-10-02 criteria provided, single submitter clinical testing This pathogenic variant is denoted RET c.1900T>C at the cDNA level, p.Cys634Arg (C634R) at the protein level, and results in the change of a Cysteine to an Arginine (TGC>CGC). This variant has been reported many times in association with multiple endocrine neoplasia type 2A (Machens 2008, Ghazi 2014, Valdes 2015, Du 2017). Variants at codon Cysteine 634 occur in ~85% of families with MEN2A (Mulligan 1994, Mulligan 1995). Functional studies show p.Cys634Arg exhibits high transforming activity (Santoro 1995, Cosci 2011). RET Cys634Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Cystenine-rich domain (Garcia-Barcelo 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000552504 SCV000658427 pathogenic Multiple endocrine neoplasia, type 2 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 634 of the RET protein (p.Cys634Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs75076352, ExAC 0.01%). This variant has been reported to co-segregate with disease in several families (PMID: 8103403, 27698838, 22900816, 23617071) and has been observed in numerous individuals with multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid cancer (MTC), and pheochromocytoma (PMID: 25027091, 25515555, 23861463, 24784869, 27539324, 8765374, 11987030, 12000816, 19825962). ClinVar contains an entry for this variant (Variation ID: 13906, 13917). This variant affects a highly conserved and functionally important cysteine amino acid residue of the RET protein. This residue is one of the most commonly altered codons in individuals affected with MEN2A (PMID: 8099202, 12000816, 21765987, 25440022). Experimental studies have shown that this missense change results in constitutive RET kinase activity and increased transforming ability in transfected cells (PMID: 15472167, 21810974, 8570194, 7824936). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014937 SCV000035193 pathogenic Multiple endocrine neoplasia, type 2a 2002-12-01 no assertion criteria provided literature only
OMIM RCV000014938 SCV000035194 pathogenic Pheochromocytoma 2002-12-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000552504 SCV000042487 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only Youngest with MTC: 17 months. Youngest with Pheo: 15 yr. Youngest with HPT: 5 yr (PMID 11900218, 18063059, and 21449769). Only one family reported as FMTC (PMID 9950371). Patients may also have cutaneous lichen amyloidosis (PMID 12864791 and 7874109). In vitro studies: RET activation (PMID 9879991, 7824936, 9230192 and 9242375). In the oldest reference, exon 11 was called exon 8. Additional references: PMID 7595171, 7915822, 18063059, 18062802 and 18976013. Has been found with other RET changes, see c.1896_1900 delinsCGTGC, c.[1900T>C;1919C>G;2098A>T], c.[1900T>C];[1942G>A], and c.[1900T>C];[1946C>T].

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