ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.1826G>A (p.Cys609Tyr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020975.6(RET):c.1826G>A (p.Cys609Tyr)
Variation ID: 13933 Accession: VCV000013933.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43113622 (GRCh38) [ NCBI UCSC ] 10: 43609070 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 8, 2017 May 1, 2024 Feb 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.1826G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Cys609Tyr missense NM_000323.2:c.1826G>A NP_000314.1:p.Cys609Tyr missense NM_001355216.2:c.1064G>A NP_001342145.1:p.Cys355Tyr missense NM_001406743.1:c.1826G>A NP_001393672.1:p.Cys609Tyr missense NM_001406744.1:c.1826G>A NP_001393673.1:p.Cys609Tyr missense NM_001406759.1:c.1826G>A NP_001393688.1:p.Cys609Tyr missense NM_001406760.1:c.1826G>A NP_001393689.1:p.Cys609Tyr missense NM_001406761.1:c.1697G>A NP_001393690.1:p.Cys566Tyr missense NM_001406762.1:c.1697G>A NP_001393691.1:p.Cys566Tyr missense NM_001406763.1:c.1826G>A NP_001393692.1:p.Cys609Tyr missense NM_001406764.1:c.1697G>A NP_001393693.1:p.Cys566Tyr missense NM_001406765.1:c.1826G>A NP_001393694.1:p.Cys609Tyr missense NM_001406766.1:c.1538G>A NP_001393695.1:p.Cys513Tyr missense NM_001406767.1:c.1538G>A NP_001393696.1:p.Cys513Tyr missense NM_001406768.1:c.1697G>A NP_001393697.1:p.Cys566Tyr missense NM_001406769.1:c.1430G>A NP_001393698.1:p.Cys477Tyr missense NM_001406770.1:c.1538G>A NP_001393699.1:p.Cys513Tyr missense NM_001406771.1:c.1388G>A NP_001393700.1:p.Cys463Tyr missense NM_001406772.1:c.1430G>A NP_001393701.1:p.Cys477Tyr missense NM_001406773.1:c.1388G>A NP_001393702.1:p.Cys463Tyr missense NM_001406774.1:c.1301G>A NP_001393703.1:p.Cys434Tyr missense NM_001406775.1:c.1100G>A NP_001393704.1:p.Cys367Tyr missense NM_001406776.1:c.1100G>A NP_001393705.1:p.Cys367Tyr missense NM_001406777.1:c.1100G>A NP_001393706.1:p.Cys367Tyr missense NM_001406778.1:c.1100G>A NP_001393707.1:p.Cys367Tyr missense NM_001406779.1:c.929G>A NP_001393708.1:p.Cys310Tyr missense NM_001406780.1:c.929G>A NP_001393709.1:p.Cys310Tyr missense NM_001406781.1:c.929G>A NP_001393710.1:p.Cys310Tyr missense NM_001406782.1:c.929G>A NP_001393711.1:p.Cys310Tyr missense NM_001406783.1:c.800G>A NP_001393712.1:p.Cys267Tyr missense NM_001406784.1:c.836G>A NP_001393713.1:p.Cys279Tyr missense NM_001406786.1:c.800G>A NP_001393715.1:p.Cys267Tyr missense NM_001406787.1:c.929G>A NP_001393716.1:p.Cys310Tyr missense NM_001406788.1:c.641G>A NP_001393717.1:p.Cys214Tyr missense NM_001406789.1:c.641G>A NP_001393718.1:p.Cys214Tyr missense NM_001406790.1:c.641G>A NP_001393719.1:p.Cys214Tyr missense NM_001406792.1:c.377G>A NP_001393721.1:p.Cys126Tyr missense NM_001406793.1:c.377G>A NP_001393722.1:p.Cys126Tyr missense NM_001406794.1:c.377G>A NP_001393723.1:p.Cys126Tyr missense NM_020629.2:c.1826G>A NP_065680.1:p.Cys609Tyr missense NM_020630.7:c.1826G>A NP_065681.1:p.Cys609Tyr missense NC_000010.11:g.43113622G>A NC_000010.10:g.43609070G>A NG_007489.1:g.41554G>A LRG_518:g.41554G>A LRG_518t1:c.1826G>A LRG_518p1:p.Cys609Tyr LRG_518t2:c.1826G>A LRG_518p2:p.Cys609Tyr P07949:p.Cys609Tyr - Protein change
- C609Y, C355Y, C279Y, C463Y, C513Y, C310Y, C477Y, C367Y, C126Y, C214Y, C267Y, C434Y, C566Y
- Other names
- p.C609Y:TGC>TAC
- Canonical SPDI
- NC_000010.11:43113621:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3523 | 3643 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Feb 28, 2017 | RCV000014958.35 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 21, 2024 | RCV000168107.27 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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May 18, 2022 | RCV000082049.34 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 18, 2023 | RCV000173889.17 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 13, 2016 | RCV000441078.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 13, 2016 | RCV000444552.9 | |
Pathogenic (2) |
criteria provided, single submitter
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Dec 20, 2018 | RCV000496009.10 | |
not provided (1) |
no classification provided
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- | RCV000509116.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 13, 2016 | RCV000424503.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 13, 2016 | RCV000431942.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2021 | RCV000562113.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 23, 2023 | RCV003460480.1 | |
RET-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Feb 16, 2024 | RCV004532352.1 |
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Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jun 09, 2015)
|
criteria provided, single submitter
Method: research
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Familial medullary thyroid carcinoma
Affected status: unknown
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000584110.1 First in ClinVar: Jul 30, 2017 Last updated: Jul 30, 2017 |
Number of individuals with the variant: 1
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Pathogenic
(May 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000786471.2
First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
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Pathogenic
(Jul 07, 2016)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000225059.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 7
Sex: mixed
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Pathogenic
(May 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967761.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 22, 2019)
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criteria provided, single submitter
Method: research
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Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI_GT
Accession: SCV000993579.1 First in ClinVar: Sep 25, 2019 Last updated: Sep 25, 2019 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 20, 2018)
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criteria provided, single submitter
Method: research
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Familial medullary thyroid carcinoma
Affected status: unknown
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI_WGS
Accession: SCV000993438.1 First in ClinVar: Sep 22, 2019 Last updated: Sep 22, 2019 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605015.5
First in ClinVar: Sep 30, 2017 Last updated: Jan 08, 2022 |
Comment:
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) … (more)
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. (less)
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Pathogenic
(Dec 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000234931.9
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
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); … (more)
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) (less)
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Pathogenic
(Oct 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001983654.2
First in ClinVar: Oct 30, 2021 Last updated: Nov 20, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Sep 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hirschsprung disease, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004208679.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000218763.13
First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Feb 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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RET-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004118283.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
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 … (more)
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://0-www-ncbi-nlm-nih-gov.brum.beds.ac.uk/clinvar/variation/13933/). In summary, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Jul 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503432.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2A
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766735.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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 (less)
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Pathogenic
(Apr 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018479.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
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 … (more)
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]. (less)
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Pathogenic
(Feb 02, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774394.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 06, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(May 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002522512.2
First in ClinVar: Jun 05, 2022 Last updated: Jan 26, 2024 |
Comment:
PP1_strong, PP4, PP5, PM1, PS3_supporting, PS4_moderate
Number of individuals with the variant: 16
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Pathogenic
(Dec 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000674737.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Feb 28, 2017)
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no assertion criteria provided
Method: literature only
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MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA, WITH HIRSCHSPRUNG DISEASE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035214.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2017 |
Comment on evidence:
Decker et al. (1998) found that Hirschsprung disease (142623) cosegregated with MEN2A (171400) in 7 (16%) of 44 families ascertained through MEN2A. The predisposing RET … (more)
Decker et al. (1998) found that Hirschsprung disease (142623) cosegregated with MEN2A (171400) in 7 (16%) of 44 families ascertained through MEN2A. The predisposing RET mutations in all 7 families had previously been reported in MEN2A or FMTC and occurred in exon 10 at codons 609, 618, or 620: C609Y, C618S, C620R, and C620W. MEN2A families with RET exon 10 cys mutations had a subsequently greater risk of developing HSCR1 than those with the more common RET exon 11 cys634 or exon 14 mutations. These findings suggested that expression of HSCR1 in MEN2A may be particular to RET exon 10 cys mutations. It appeared that oncogenic activation of RET alone was insufficient to account for coexpression of the diseases. (less)
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Multiple endocrine neoplasia type 2A
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000510473.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Multiple endocrine neoplasia type 2B
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000510472.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Medullary thyroid carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000510474.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Multiple endocrine neoplasia type 4
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000510475.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Multiple endocrine neoplasia, type 1
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000510476.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Multiple endocrine neoplasia type 2A
Familial medullary thyroid carcinoma
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000607362.1
First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017 |
Comment:
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 … (more)
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. (less)
Indication for testing: Family Testing
Age: 40-49 years
Sex: female
Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic
Date variant was reported to submitter: 2016-11-14
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations. | Elisei R | Genes | 2019 | PMID: 31510104 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
p.Ser891Ala RET gene mutations in medullary thyroid cancer: Phenotypical and genealogical characterization of 28 apparently unrelated kindreds and founder effect uncovering in Northern Italy. | Giacché M | Human mutation | 2019 | PMID: 30927507 |
Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study. | Maciel RMB | Endocrine connections | 2019 | PMID: 30763276 |
Genomic sequencing identifies secondary findings in a cohort of parent study participants. | Thompson ML | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29790872 |
Disease-modifying polymorphisms and C609Y mutation of RET associated with high penetrance of phaeochromocytoma and low rate of MTC in MEN2A. | Speak R | Endocrinology, diabetes & metabolism case reports | 2016 | PMID: 27994876 |
Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. | Wells SA Jr | Thyroid : official journal of the American Thyroid Association | 2015 | PMID: 25810047 |
Prevalence by age and predictors of medullary thyroid cancer in patients with lower risk germline RET proto-oncogene mutations. | Rich TA | Thyroid : official journal of the American Thyroid Association | 2014 | PMID: 24617864 |
Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2. | Wagner SM | Clinics (Sao Paulo, Brazil) | 2012 | PMID: 22584710 |
Prevalence of germline mutations in patients with pheochromocytoma or abdominal paraganglioma and sporadic presentation: a population-based study in Western Sweden. | Muth A | World journal of surgery | 2012 | PMID: 22270996 |
Hirschsprung's disease and medullary thyroid carcinoma: 15-year experience with molecular genetic screening of the RET proto-oncogene. | Vaclavikova E | Pediatric surgery international | 2012 | PMID: 21986619 |
Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. | Frank-Raue K | Human mutation | 2011 | PMID: 20979234 |
Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. | Romei C | European journal of endocrinology | 2010 | PMID: 20516206 |
RET proto-oncogene testing in infants presenting with Hirschsprung disease identifies 2 new multiple endocrine neoplasia 2A kindreds. | Fialkowski EA | Journal of pediatric surgery | 2008 | PMID: 18206480 |
Pheochromocytoma penetrance varies by RET mutation in MEN 2A. | Quayle FJ | Surgery | 2007 | PMID: 18063059 |
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. | Paszko Z | Cancer investigation | 2007 | PMID: 18058472 |
A newly detected mutation of the RET protooncogene in exon 8 as a cause of multiple endocrine neoplasia type 2A. | Bethanis S | Hormones (Athens, Greece) | 2007 | PMID: 17704047 |
Evaluation of potential mechanisms underlying genotype-phenotype correlations in multiple endocrine neoplasia type 2. | Mise N | Oncogene | 2006 | PMID: 16715139 |
A novel Czech kindred with familial medullary thyroid carcinoma and Hirschsprung's disease. | Dvoráková S | Journal of pediatric surgery | 2005 | PMID: 15991157 |
Nine novel germline gene variants in the RET proto-oncogene identified in twelve unrelated cases. | Ahmed SA | The Journal of molecular diagnostics : JMD | 2005 | PMID: 15858153 |
Medullary thyroid cancer in a patient with Hirschsprung disease with a C609Y germline RET-mutation. | de Groot JW | Journal of pediatric gastroenterology and nutrition | 2005 | PMID: 15699703 |
Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. | Jindrichová S | The Journal of endocrinology | 2004 | PMID: 15531714 |
Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis. | de Graaff E | Genes & development | 2001 | PMID: 11562352 |
RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems. | Hofstra RM | Human mutation | 2000 | PMID: 10790203 |
The Glu632-Leu633 deletion in cysteine rich domain of Ret induces constitutive dimerization and alters the processing of the receptor protein. | Bongarzone I | Oncogene | 1999 | PMID: 10490816 |
Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function? | Takahashi M | Human mutation | 1999 | PMID: 10220148 |
Oncological implications of RET gene mutations in Hirschsprung's disease. | Sijmons RH | Gut | 1998 | PMID: 9824583 |
Molecular mechanisms of development of multiple endocrine neoplasia 2 by RET mutations. | Takahashi M | Journal of internal medicine | 1998 | PMID: 9681851 |
Occurrence of MEN 2a in familial Hirschsprung's disease: a new indication for genetic testing of the RET proto-oncogene. | Decker RA | Journal of pediatric surgery | 1998 | PMID: 9498388 |
Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. | Decker RA | Human molecular genetics | 1998 | PMID: 9384613 |
Age-Related Disease Penetrance in a Large Medullary Thyroid Cancer Family With a Codon 609 RET Gene Mutation. | Halling KC | Molecular diagnosis : a journal devoted to the understanding of human disease through the clinical application of molecular biology | 1997 | PMID: 10462620 |
Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype. | Ito S | Cancer research | 1997 | PMID: 9230192 |
Genetic testing in medullary thyroid carcinoma syndromes: mutation types and clinical significance. | Heshmati HM | Mayo Clinic proceedings | 1997 | PMID: 9146685 |
The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. | Eng C | JAMA | 1996 | PMID: 8918855 |
Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. | Wohllk N | The Journal of clinical endocrinology and metabolism | 1996 | PMID: 8855832 |
RET mutation screening in MEN2 patients and discovery of a novel mutation in a sporadic medullary thyroid carcinoma. | Jhiang SM | Thyroid : official journal of the American Thyroid Association | 1996 | PMID: 8733882 |
Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. | Angrist M | Human molecular genetics | 1995 | PMID: 7633441 |
Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. | Mulligan LM | Nature genetics | 1994 | PMID: 7907913 |
RET proto-oncogene mutations in inherited and sporadic medullary thyroid cancer. | Blaugrund JE | Human molecular genetics | 1994 | PMID: 7849720 |
http://docm.genome.wustl.edu/variants/ENST00000340058:c.1826G>A | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RET | - | - | - | - |
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Text-mined citations for rs77939446 ...
HelpRecord last updated May 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.