ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.1853G>T (p.Cys618Phe)
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.1853G>T (p.Cys618Phe)
Variation ID: 24902 Accession: VCV000024902.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43113649 (GRCh38) [ NCBI UCSC ] 10: 43609097 (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 Oct 9, 2016 May 1, 2024 Jan 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.1853G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Cys618Phe missense NM_000323.2:c.1853G>T NP_000314.1:p.Cys618Phe missense NM_001355216.2:c.1091G>T NP_001342145.1:p.Cys364Phe missense NM_001406743.1:c.1853G>T NP_001393672.1:p.Cys618Phe missense NM_001406744.1:c.1853G>T NP_001393673.1:p.Cys618Phe missense NM_001406759.1:c.1853G>T NP_001393688.1:p.Cys618Phe missense NM_001406760.1:c.1853G>T NP_001393689.1:p.Cys618Phe missense NM_001406761.1:c.1724G>T NP_001393690.1:p.Cys575Phe missense NM_001406762.1:c.1724G>T NP_001393691.1:p.Cys575Phe missense NM_001406763.1:c.1853G>T NP_001393692.1:p.Cys618Phe missense NM_001406764.1:c.1724G>T NP_001393693.1:p.Cys575Phe missense NM_001406765.1:c.1853G>T NP_001393694.1:p.Cys618Phe missense NM_001406766.1:c.1565G>T NP_001393695.1:p.Cys522Phe missense NM_001406767.1:c.1565G>T NP_001393696.1:p.Cys522Phe missense NM_001406768.1:c.1724G>T NP_001393697.1:p.Cys575Phe missense NM_001406769.1:c.1457G>T NP_001393698.1:p.Cys486Phe missense NM_001406770.1:c.1565G>T NP_001393699.1:p.Cys522Phe missense NM_001406771.1:c.1415G>T NP_001393700.1:p.Cys472Phe missense NM_001406772.1:c.1457G>T NP_001393701.1:p.Cys486Phe missense NM_001406773.1:c.1415G>T NP_001393702.1:p.Cys472Phe missense NM_001406774.1:c.1328G>T NP_001393703.1:p.Cys443Phe missense NM_001406775.1:c.1127G>T NP_001393704.1:p.Cys376Phe missense NM_001406776.1:c.1127G>T NP_001393705.1:p.Cys376Phe missense NM_001406777.1:c.1127G>T NP_001393706.1:p.Cys376Phe missense NM_001406778.1:c.1127G>T NP_001393707.1:p.Cys376Phe missense NM_001406779.1:c.956G>T NP_001393708.1:p.Cys319Phe missense NM_001406780.1:c.956G>T NP_001393709.1:p.Cys319Phe missense NM_001406781.1:c.956G>T NP_001393710.1:p.Cys319Phe missense NM_001406782.1:c.956G>T NP_001393711.1:p.Cys319Phe missense NM_001406783.1:c.827G>T NP_001393712.1:p.Cys276Phe missense NM_001406784.1:c.863G>T NP_001393713.1:p.Cys288Phe missense NM_001406786.1:c.827G>T NP_001393715.1:p.Cys276Phe missense NM_001406787.1:c.956G>T NP_001393716.1:p.Cys319Phe missense NM_001406788.1:c.668G>T NP_001393717.1:p.Cys223Phe missense NM_001406789.1:c.668G>T NP_001393718.1:p.Cys223Phe missense NM_001406790.1:c.668G>T NP_001393719.1:p.Cys223Phe missense NM_001406792.1:c.404G>T NP_001393721.1:p.Cys135Phe missense NM_001406793.1:c.404G>T NP_001393722.1:p.Cys135Phe missense NM_001406794.1:c.404G>T NP_001393723.1:p.Cys135Phe missense NM_020629.2:c.1853G>T NP_065680.1:p.Cys618Phe missense NM_020630.7:c.1853G>T NP_065681.1:p.Cys618Phe missense NC_000010.11:g.43113649G>T NC_000010.10:g.43609097G>T NG_007489.1:g.41581G>T LRG_518:g.41581G>T LRG_518t1:c.1853G>T LRG_518p1:p.Cys618Phe LRG_518t2:c.1853G>T LRG_518p2:p.Cys618Phe P07949:p.Cys618Phe - Protein change
- C364F, C135F, C276F, C522F, C288F, C319F, C376F, C486F, C223F, C472F, C575F, C443F
- Other names
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- Canonical SPDI
- NC_000010.11:43113648:G:T
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
3592 | 3714 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2020 | RCV000255102.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2022 | RCV000571381.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 13, 2023 | RCV000548660.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 5, 2024 | RCV004018656.1 |
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
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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
(Feb 01, 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: SCV001474221.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The RET c.1853G>T; p.Cys618Phe variant (rs79781594) is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 2A (MEN2A) or … (more)
The RET c.1853G>T; p.Cys618Phe variant (rs79781594) is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 2A (MEN2A) or medullary thyroid cancer (MTC) (Egawa 1998, Frank-Raue 2011, Hedayati 2011, Mathiesen 2017). Individuals with this variant show age-related penetrance for MTC and pheochromocytoma, and variants in this codon confer a moderate risk for developing MTC (Frank-Raue 2011, Wells 2015). This variant is absent from general population databases (Exome Variant Server, 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). Indeed, other amino acid substitutions at this codon (Arg, Gly, Ser, and Tyr) have been reported in individuals with MTC or MEN2A and are considered disease-causing (Egawa 1998, Frank-Raue 2011, Hedayati 2011, Mathiesen 2017, Wells 2015). Based on available information, the p.Cys618Phe variant is considered to be 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. Egawa S et al. Genotype-phenotype correlation of patients with multiple endocrine neoplasia type 2 in Japan. Jpn J Clin Oncol. 1998 Oct;28(10):590-6. 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. Hedayati M et al. Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma. J Thyroid Res. 2011;2011:264248. 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. Mathiesen JS et al. Founder Effect of the RETC611Y Mutation in Multiple Endocrine Neoplasia 2A in Denmark: A Nationwide Study. Thyroid. 2017 Dec;27(12):1505-1510. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. (less)
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Pathogenic
(Mar 13, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000658421.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 618 of the RET protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 618 of the RET protein (p.Cys618Phe). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys618 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7915165, 9498388, 20979234, 22068382, 25628771; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 24902). This missense change has been observed in individuals with medullary thyroid cancer (MTC) and multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid cancer (FMTC) (PMID: 8807338, 9839497, 18058472, 18063059, 21765987). This variant is not present in population databases (gnomAD no frequency). (less)
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Pathogenic
(Jan 05, 2024)
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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: SCV004930806.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 29656518, 20979234, 21765987, 18058472, 18063059, … (more)
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 29656518, 20979234, 21765987, 18058472, 18063059, 25810047]. Functional studies indicate this variant impacts protein function [PMID: 30884088]. (less)
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Pathogenic
(Mar 15, 2017)
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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: SCV000322341.6
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
Comment:
The C618F variant in the RET gene has been reported previously in multiple individuals with medullary thyroid carcinoma and/or pheochromocytoma (Egawa et al., 1998; Frank-Raue … (more)
The C618F variant in the RET gene has been reported previously in multiple individuals with medullary thyroid carcinoma and/or pheochromocytoma (Egawa et al., 1998; Frank-Raue et al., 2011; Kim et al., 2011), in multiple families with multiple endocrine neoplasia 2A (Edery et al., 1997; Paszko et al., 2007; Quayle et al., 2007), and was reported as a common pathogenic variant conferring moderate risk for medullary thyroid carcinoma (Wells et al., 2015). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C618F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs within a mutation hotspot at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (C618S, C618G, C618R, C618Y) have been reported in association with RET-related disorders, supporting the functional importance of this region of the protein (Donis-Keller et al., 1993; Mulligan et al., 1993; Blaugrund et al., 1994). Based on currently available evidence, we consider C618F to be pathogenic. (less)
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Pathogenic
(Oct 13, 2022)
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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: SCV000674902.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.C618F pathogenic mutation (also known as c.1853G>T), located in coding exon 10 of the RET gene, results from a G to T substitution at … (more)
The p.C618F pathogenic mutation (also known as c.1853G>T), located in coding exon 10 of the RET gene, results from a G to T substitution at nucleotide position 1853. The cysteine at codon 618 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This pathogenic mutation has been reported in numerous individuals and/or families fulfilling criteria for a clinical diagnosis of multiple endocrine neoplasia type 2A (MEN2A) (Kambouris M et al. Hum. Mutat.1996;8:64-70; Quayle FJ et al. Surgery, 2007 Dec;142:800-5; discussion 805.e1; Paszko Z et al. Cancer Invest., 2007 Dec;25:742-9; Hedayati M et al. J Thyroid Res. 2011 Jun;2011:264248; Kim DD et al. Thyroid. 2011 Mar;21:325-6; Frank-Raue K et al. Hum. Mutat. 2011 Jan;32:51-8). Additionally, several other pathogenic mutations have been reported at this same codon: p.C618S, p.C618G, p.C618R, and p.C618Y. Furthermore, this mutation has been classified as conferring "moderate risk" for MTC by the American Thyroid Association (Kloos et al. Thyroid. 2009 Jun;19:565-612; Wells SA et al. Thyroid. 2015 Jun;25:567-610). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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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 |
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Mice conditionally expressing RET(C618F) mutation display C cell hyperplasia and hyperganglionosis of the enteric nervous system. | Okamoto M | Genesis (New York, N.Y. : 2000) | 2019 | PMID: 30884088 |
Genotype-specific progression of hereditary medullary thyroid cancer. | Machens A | Human mutation | 2018 | PMID: 29656518 |
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 |
Molecular diagnosis and comprehensive treatment of multiple endocrine neoplasia type 2 in Southeastern Chinese. | Zhao JQ | Hereditary cancer in clinical practice | 2015 | PMID: 25628771 |
Case report: a p.C618S RET proto-oncogene germline mutation in a large Chinese pedigree with familial medullary thyroid carcinoma. | Qi XP | Familial cancer | 2012 | PMID: 22068382 |
Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma. | Hedayati M | Journal of thyroid research | 2011 | PMID: 21765987 |
Indolent medullary thyroid cancer with a RET proto-oncogene Cys618Phe mutation presenting as sporadic unilateral pheochromocytoma in a 55-year-old Korean woman. | Kim DD | Thyroid : official journal of the American Thyroid Association | 2011 | PMID: 21254918 |
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 |
Medullary thyroid cancer: management guidelines of the American Thyroid Association. | American Thyroid Association Guidelines Task Force | Thyroid : official journal of the American Thyroid Association | 2009 | PMID: 19469690 |
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 |
Genotype-phenotype correlation of patients with multiple endocrine neoplasia type 2 in Japan. | Egawa S | Japanese journal of clinical oncology | 1998 | PMID: 9839497 |
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 |
RET in human development and oncogenesis. | Edery P | BioEssays : news and reviews in molecular, cellular and developmental biology | 1997 | PMID: 9174404 |
Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial medullary thyroid cancer [FMTC] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations. | Kambouris M | Human mutation | 1996 | PMID: 8807338 |
Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests. | Xue F | Human molecular genetics | 1994 | PMID: 7915165 |
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Text-mined citations for rs79781594 ...
HelpRecord last updated Oct 13, 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.