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

gnomAD frequency: 0.00001  dbSNP: rs77939446

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168107	SCV000218763	pathogenic	Multiple endocrine neoplasia, type 2	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 609 of the RET protein (p.Cys609Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma, and Hirschsprung disease (PMID: 19472011, 24617864). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13933). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RET function (PMID: 9230192, 9681851, 16715139, 21986619). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000082049	SCV000225059	pathogenic	not provided	2016-07-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000082049	SCV000234931	pathogenic	not provided	2021-12-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: significantly reduced transforming activity (Ito 1997); 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: 16715139, 22270996, 30763276, 20516206, 14633923, 18206480, 17021738, 18063059, 7907913, 9230192, 7849720, 15699703, 21986619, 9384613, 19472011, 27994876, 24705026, 10220148, 7595168, 18984779, 7633441, 20979234, 8901418, 12915470, 28647780, 29790872, 30927507, 31510104, 9498388, 12686527, 15531714, 10462620, 8855832, 31447099, 30787465, 33087929)
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	RCV000082049	SCV000605015	pathogenic	not provided	2020-10-07	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; pathogenic variants resulting in the loss of a cysteine residue are common in these repeats and are predicted to disrupt protein structure, resulting 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	2021-12-06	criteria provided, single submitter	clinical testing	The p.C609Y pathogenic mutation (also known as c.1826G>A), located in coding exon 10 of the RET gene, results from a G to A substitution at nucleotide position 1826. The cysteine at codon 609 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been identified in multiple MEN2A patients and families with Hirschsprung disease (HSCR1), familial medullary thyroid cancer (FMTC), and pheochromocytoma (Blaugrund JE et al. Hum. Mol. Genet. 1994 Oct;3(10):1895-7; Decker RA et al. Hum. Mol. Genet. 1998 Jan;7(1):129-34; Fialkowski EA et al. J. Pediatr. Surg. 2008 Jan;43(1):188-90; Vaclavikova et al. Pediatr. Surg. Int. 2012 Feb;28(2):123-8; Muth et al. World J. Surg. 2012 Jun;36(6):1389-94; Speak R et al. Endocrinol Diabetes Metab. Case Rep. 2016 Nov;2016; Giacché M et al. Hum Mutat, 2019 07;40:926-937). The American Thyroid Association Guidelines Task Force has provided recommendations for individuals with RET gene mutations (Wells SA et al. Thyroid. 2015 Jun; 25(6):567-610). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000173889	SCV000786471	pathogenic	Multiple endocrine neoplasia type 2A	2018-05-08	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168107	SCV001983654	pathogenic	Multiple endocrine neoplasia, type 2	2023-10-04	criteria provided, single submitter	clinical testing	Variant summary: RET c.1826G>A (p.Cys609Tyr) 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 4e-06 in 248472 control chromosomes. c.1826G>A has been widely reported in the literature as a well-established disease causing variant in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma and in those with Hirschsprung disease (example, Balugrund_1994, Halling_1997, Decker_1998, Ahmed_2005, Fialkowski_2008, Vaclavikova_2012). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in enhanced cell cycle progression supported by demonstration of increased cell proliferation in-vivo and in-vitro (example, Mise_2006). The following publications have been ascertained in the context of this evaluation (PMID: 15858153, 7849720, 9498388, 10462620, 9230192, 16715139, 18206480, 21986619). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000082049	SCV002503432	pathogenic	not provided	2021-07-20	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000082049	SCV002522512	pathogenic	not provided	2022-05-18	criteria provided, single submitter	clinical testing	PP1_strong, PP4, PP5, PM1, PS3_supporting, PS4_moderate
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000173889	SCV002766735	pathogenic	Multiple endocrine neoplasia type 2A	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3., this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function variants are associated with Hirschsprung disease (MIM#142623), while gain of function variants cause multiple endocrine neoplasia IIA (MEN2A, MIM#171400), multiple endocrine neoplasia IIB (MEN2B, MIM#162300), and medullary thyroid carcinoma (MTC, MIM#155240). A subset of RET cysteine variants, sometimes referred to as Janus variants, can lead to a partial loss-of-function phenotype, as well as to oncogenic effects (PMID: 22584710, OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in a missense hotspot region in the extracellular cysteine rich domain (PMID: 22584710, DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Alternative amino acid changes to arginine, phenylalanine, glycine, and serine, have been reported in individuals with MEN2A (PMID: 20979234, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with multiple endocrine neoplasia IIA (MEN2A), familial medullary thyroid carcinoma, and Hirschsprung disease (PMID: 20979234, PMID: 8733882, PMID: 7633441, ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000082049	SCV002774394	pathogenic	not provided	2017-02-02	criteria provided, single submitter	clinical testing	This variant is located at one of the hot spots for pathogenic variants associated with MEN 2A and FMTC. In the published literature, this variant has been reported in individuals with MEN 2A or FMTC (PMID: 7849720 (1994), 7907913 (1994), 9146685 (1997), 18206480 (2008)). It has also been reported in individuals with Hirschsprung disease (PMID: 7633441 (1995), 9384613 (1998), 9824583 (1998)). In a functional study, this variant had a deleterious effect on RET protein function (PMID: 9230192 (1997)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV000173889	SCV004018479	pathogenic	Multiple endocrine neoplasia type 2A	2023-04-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9230192, 16715139]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19472011, 27994876, 15858153, 21986619, 20979234, 18206480, 25810047].
Baylor Genetics	RCV003460480	SCV004208679	pathogenic	Hirschsprung disease, susceptibility to, 1	2024-03-20	criteria provided, single submitter	clinical testing
OMIM	RCV000014958	SCV000035214	pathogenic	MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA, WITH HIRSCHSPRUNG DISEASE	2017-02-28	no assertion criteria provided	literature only
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.
PreventionGenetics, part of Exact Sciences	RCV004532352	SCV004118283	pathogenic	RET-related disorder	2024-02-16	no assertion criteria provided	clinical testing	The RET c.1826G>A variant is predicted to result in the amino acid substitution p.Cys609Tyr. This variant has previously been reported in individuals who have multiple endocrine neoplasia, familial medullary thyroid carcinoma and phaeochromocytoma who may also have Hirschsprung disease (Blaugrund et al. 1994. PubMed ID: 7849720. Vaciavikova et al. 2012. PubMed ID: 21986619; Muth et al. 2012. PubMed ID: 22270996). Reduced penetrance has been reported for p.Cys609Tyr and multiple other p.Cys609 variants. In addition, age-related penetrance and clinical phenotype variability have also been reported for RET p.Cys609 variants, including p.Cys609Tyr (Frank-Raue et al. 2011. PubMed ID: 20979234). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13933/). In summary, this variant is interpreted as pathogenic.