ClinVar Miner

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

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163338 SCV000213872 pathogenic Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing 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
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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999911 SCV000605036 pathogenic not specified 2018-07-25 criteria provided, single submitter clinical testing
Invitae RCV000552504 SCV000658427 pathogenic Multiple endocrine neoplasia, type 2 2019-11-27 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.
3DMed Clinical Laboratory Inc RCV000677899 SCV000804061 pathogenic Thyroid carcinoma 2017-10-26 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000082051 SCV000842751 pathogenic not provided 2018-05-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000014937 SCV001338566 pathogenic Multiple endocrine neoplasia, type 2a 2020-04-03 criteria provided, single submitter clinical testing Variant summary: RET c.1900T>C (p.Cys634Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 247534 control chromosomes (gnomAD). c.1900T>C has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2A, medullary thyroid cancer and pheochromocytoma (e.g. Valdes_2015, Pandit_2016, Zou_2016). These data indicate that the variant is very likely to be associated with disease. This amino acid change was found to be the most common change found at this codon in individuals affected with MEN2A (Birla_2014). In functional studies, the variant was found to have constitutive kinase activity and increased transforming ability (e.g. Cosci_2011, Santoro_1995). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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].
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
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

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