ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1826G>A (p.Cys609Tyr) (rs77939446)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168107 SCV000218763 pathogenic Multiple endocrine neoplasia, type 2 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 609 of the RET protein (p.Cys609Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous patients and families affected with multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma, and Hirschsprung disease, and is clearly defined as a MEN2A causative allele (PMID: 24617864, 19472011). ClinVar contains an entry for this variant (Variation ID: 13933). Experimental studies have shown that this missense change disrupts proper RET function, and leads to enhanced cell-cycle progression and cell proliferation in vitro and in vivo (PMID: 9681851, 16715139, 9230192, 21986619). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082049 SCV000225059 pathogenic not provided 2016-07-07 criteria provided, single submitter clinical testing
GeneDx RCV000082049 SCV000234931 pathogenic not provided 2018-05-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted RET c.1826G>A at the cDNA level, p.Cys609Tyr (C609Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant has been published numerous times in association with multiple endocine neoplasia type 2A (MEN2A), familial medullary thyroid carcinoma (FMTC), and Hirschsprung disease (HSCR) (Blaugrund 1994, Decker 1998, de Groot 2005, Calva 2009, Frank-Raue 2011, Speak 2016). In addition, functional studies show Cys609Tyr to significantly reduce the transforming activity of the RET gene (Ito 1997). RET Cys609Tyr was not observed in large population cohorts (Lek 2016). Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RET Cys609Tyr occurs at a position that is conserved across species and is located in the extracellular, cysteine-rich domain (Garcia-Barcelo 2004). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000496009 SCV000584110 pathogenic Familial medullary thyroid carcinoma 2015-06-09 criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000999726 SCV000605015 pathogenic not specified 2018-09-22 criteria provided, single submitter clinical testing The RET c.1826G>A; p.Cys609Tyr variant (rs77939446) has been reported in multiple patients diagnosed with multiple endocrine neoplasia type 2A (MEN2A), familial medullary thyroid carcinoma (FMTC) and Hirschsprung disease, and is considered a variant of moderate risk by the American Thyroid Association (Wells 2015). The variant is listed in the ClinVar database (Variation ID: 13933) and is found on only one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant lies within a cysteine rich domain, and pathogenic variants resulting in the loss of a cysteine residue are common in these repeats and are predicted to disrupt protein structure and result in aberrant activation of the RET protein (Amoresano 2005, Chappuis-Flament 1998, Ito 1997). Additionally, other amino acid substitutions at this codon (Arg, Gly, Phe, Ser, Trp) have been reported in individuals with MEN2A and FMTC and are considered pathogenic (Frank-Raue 2011, Paszko 2007, Romei 2010, Siegelman 1997). Based on available information, the p.Cys609Tyr variant is considered pathogenic. REFERENCES Amoresano A et al. Direct interactions among Ret, GDNF and GFRalpha1 molecules reveal new insights into the assembly of a functional three-protein complex. Cell Signal. 2005 Jun;17(6):717-27. Chappuis-Flament S et al. Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines. Oncogene. 1998 Dec 3;17(22):2851-61. 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 Jan;32(1):51-8. Ito S et al. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype. Cancer Res. 1997 Jul 15;57(14):2870-2. Paszko Z et al. The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their unaffected kindred's from Central Poland. Cancer Invest. 2007 Dec;25(8):742-9. Romei C et al. Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol. 2010 Aug;163(2):301-8. Siegelman M et al. Rapid, nonradioactive screening for mutations in exons 10, 11, and 16 of the RET protooncogene associated with inherited medullary thyroid carcinoma. Clin Chem. 1997 Mar;43(3):453-7. Wells S et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015 25(6):567-610.
Ambry Genetics RCV000562113 SCV000674737 pathogenic Hereditary cancer-predisposing syndrome 2018-11-26 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Well-characterized mutation at same position;Other strong data supporting pathogenic classification
Counsyl RCV000173889 SCV000786471 pathogenic Multiple endocrine neoplasia, type 2a 2018-05-08 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000168107 SCV000967761 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 criteria provided, single submitter clinical testing The p.Cys609Tyr variant in RET (ClinVar variation ID# 13933) is a well-known, pa thogenic variant that causes multiple endocrine neoplasia type 2A (MEN2A) (Marqu ard 2015: ReneReviews). This variant has been reported in more than 15 families with a range of RET-associated presentations including MEN2A, and medullary thyr oid carcinoma (MTC), and Hirschsprung disease (Blaugrund 1994, Eng 1996, Decker 1998, de Groot 2005, Ahmed 2005, Quayle 2007, Calva 2009). The variant segregate d with the disease in at least 9 affected relatives (Calva 2009, Ahmed 2005). Ot her data supporting pathogenicity includes rarity in population databases (1/110 672 of European chromosomes, Genome Aggregation Database (gnomAD, http://gnomad. broadinstitute.org/; dbSNP rs77939446) and functional studies (Ito 1997, Mise 20 06). In summary, this variant meets criteria to be classified as pathogenic for MEN2A in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4; PP1_Stron g; PM2; PS3_Moderate; PP3.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000496009 SCV000993438 pathogenic Familial medullary thyroid carcinoma 2018-12-20 criteria provided, single submitter research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000173889 SCV000993579 pathogenic Multiple endocrine neoplasia, type 2a 2019-07-22 criteria provided, single submitter research
OMIM RCV000014958 SCV000035214 pathogenic MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA, WITH HIRSCHSPRUNG DISEASE 2017-02-28 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000168107 SCV000042444 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Youngest with MTC: 14 yr. Youngest with Pheo: 27 yr. Youngest with HPT: 38 yr. Patients may also have HSCR or corneal nerve thickening (PMID 9498388, 8855832, 7633441, 12686527, 17021738 and 15531714). In vitro studies: RET activation (PMID 9230192). Additional references: PMID 20979234, 19472011, 10462620, 18063059 and 9384613. Has been found with another RET change, see c.[1826G>A];[1846_1848delGAG].
Database of Curated Mutations (DoCM) RCV000441078 SCV000510472 likely pathogenic Multiple endocrine neoplasia, type 2b 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000173889 SCV000510473 likely pathogenic Multiple endocrine neoplasia, type 2a 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431942 SCV000510474 likely pathogenic Medullary thyroid carcinoma 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444552 SCV000510475 likely pathogenic Multiple endocrine neoplasia, type 4 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424503 SCV000510476 likely pathogenic Multiple endocrine neoplasia, type 1 2016-05-13 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000509116 SCV000607362 not provided Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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