ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.1900T>G (p.Cys634Gly)
Germline
Classification
Help
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.
(11)
Help
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.
Pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020975.6(RET):c.1900T>G (p.Cys634Gly)
Variation ID: 13908 Accession: VCV000013908.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43114500 (GRCh38) [ NCBI UCSC ] 10: 43609948 (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 Aug 25, 2024 Feb 2, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.1900T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Cys634Gly missense NM_000323.2:c.1900T>G NP_000314.1:p.Cys634Gly missense NM_001355216.2:c.1138T>G NP_001342145.1:p.Cys380Gly missense NM_001406743.1:c.1900T>G NP_001393672.1:p.Cys634Gly missense NM_001406744.1:c.1900T>G NP_001393673.1:p.Cys634Gly missense NM_001406759.1:c.1900T>G NP_001393688.1:p.Cys634Gly missense NM_001406760.1:c.1900T>G NP_001393689.1:p.Cys634Gly missense NM_001406761.1:c.1771T>G NP_001393690.1:p.Cys591Gly missense NM_001406762.1:c.1771T>G NP_001393691.1:p.Cys591Gly missense NM_001406764.1:c.1771T>G NP_001393693.1:p.Cys591Gly missense NM_001406766.1:c.1612T>G NP_001393695.1:p.Cys538Gly missense NM_001406767.1:c.1612T>G NP_001393696.1:p.Cys538Gly missense NM_001406769.1:c.1504T>G NP_001393698.1:p.Cys502Gly missense NM_001406770.1:c.1612T>G NP_001393699.1:p.Cys538Gly missense NM_001406771.1:c.1462T>G NP_001393700.1:p.Cys488Gly missense NM_001406772.1:c.1504T>G NP_001393701.1:p.Cys502Gly missense NM_001406773.1:c.1462T>G NP_001393702.1:p.Cys488Gly missense NM_001406774.1:c.1375T>G NP_001393703.1:p.Cys459Gly missense NM_001406775.1:c.1174T>G NP_001393704.1:p.Cys392Gly missense NM_001406776.1:c.1174T>G NP_001393705.1:p.Cys392Gly missense NM_001406777.1:c.1174T>G NP_001393706.1:p.Cys392Gly missense NM_001406778.1:c.1174T>G NP_001393707.1:p.Cys392Gly missense NM_001406779.1:c.1003T>G NP_001393708.1:p.Cys335Gly missense NM_001406780.1:c.1003T>G NP_001393709.1:p.Cys335Gly missense NM_001406781.1:c.1003T>G NP_001393710.1:p.Cys335Gly missense NM_001406782.1:c.1003T>G NP_001393711.1:p.Cys335Gly missense NM_001406783.1:c.874T>G NP_001393712.1:p.Cys292Gly missense NM_001406784.1:c.910T>G NP_001393713.1:p.Cys304Gly missense NM_001406785.1:c.883T>G NP_001393714.1:p.Cys295Gly missense NM_001406786.1:c.874T>G NP_001393715.1:p.Cys292Gly missense NM_001406788.1:c.715T>G NP_001393717.1:p.Cys239Gly missense NM_001406789.1:c.715T>G NP_001393718.1:p.Cys239Gly missense NM_001406790.1:c.715T>G NP_001393719.1:p.Cys239Gly missense NM_001406791.1:c.595T>G NP_001393720.1:p.Cys199Gly missense NM_001406792.1:c.451T>G NP_001393721.1:p.Cys151Gly missense NM_001406793.1:c.451T>G NP_001393722.1:p.Cys151Gly missense NM_001406794.1:c.451T>G NP_001393723.1:p.Cys151Gly missense NM_020629.2:c.1900T>G NP_065680.1:p.Cys634Gly missense NM_020630.7:c.1900T>G NP_065681.1:p.Cys634Gly missense NC_000010.11:g.43114500T>G NC_000010.10:g.43609948T>G NG_007489.1:g.42432T>G LRG_518:g.42432T>G LRG_518t1:c.1900T>G LRG_518p1:p.Cys634Gly LRG_518t2:c.1900T>G LRG_518p2:p.Cys634Gly P07949:p.Cys634Gly - Protein change
- C634G, C380G, C304G, C335G, C488G, C199G, C239G, C295G, C392G, C502G, C538G, C151G, C459G, C591G, C292G
- Other names
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p.C634G:TGC>GGC
- Canonical SPDI
- NC_000010.11:43114499:T:G
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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.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
3594 | 3716 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
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May 9, 2002 | RCV000014923.28 | |
| Pathogenic (1) |
no assertion criteria provided
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May 9, 2002 | RCV000014922.28 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 2, 2024 | RCV000182581.16 | |
| Pathogenic (1) |
criteria provided, single submitter
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Dec 5, 2023 | RCV000654584.9 | |
| Pathogenic (1) |
criteria provided, single submitter
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Mar 3, 2023 | RCV001013616.5 | |
| Pathogenic (1) |
criteria provided, single submitter
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Apr 2, 2020 | RCV001310209.2 | |
| Pathogenic (1) |
criteria provided, single submitter
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Apr 25, 2021 | RCV001420921.2 |
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
(Jan 03, 2018)
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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: SCV000605032.2
First in ClinVar: Sep 30, 2017 Last updated: Feb 17, 2019 |
Comment:
The RET c.1900T>G;p.Cys634Gly variant (rs75076352) has been published in multiple individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma … (more)
The RET c.1900T>G;p.Cys634Gly variant (rs75076352) has been published in multiple individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (FMTC) and at least one individual with pheochromocytoma (American Thyroid Association Guidelines Task Force 2009, Hedayati 2011, Neumann 2002, Wells 2015). The variant is listed in the ClinVar database (Variation ID: 13908), but is not listed in the Genome Aggregation Database. The cysteine at codon 634 is conserved across a variety of species and computational programs (PolyPhen2, SIFT) predict this variant is deleterious to protein function. Considering available information, this variant is classified as pathogenic. References: American Thyroid Association Guidelines Task Force. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 19(6):565-612. 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. 2011:264248. Neumann HP et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002 346(19):1459-66. 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
(Apr 15, 2016)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449636.1
First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020 |
Number of individuals with the variant: 10
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Pathogenic
(Apr 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
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MEN2 phenotype: Unclassified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001623374.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment:
Variant summary: RET c.1900T>G (p.Cys634Gly) 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.1900T>G (p.Cys634Gly) 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 most frequent mutations in the RET proto-oncogene have been found in five cysteine codons 609, 611, 618, and 620 of exon 10 and codon 634 of exon 11. The variant was absent in 247534 control chromosomes. c.1900T>G has been widely reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Phaeochromocytoma/Medullary Carcinoma of the Thyroid/ multiple endocrine neoplasia type 2A (MEN 2A)-cutaneous lichen amyloidosis (example, Mulligan_1993, Neumann_2002, Sanz_2009, Hedayati_2011, Qi_2018, Maciel_2019). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 21, 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: SCV000234933.12
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant … (more)
Not observed 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: 24466223, 26267327, 30763276, 27349013, 28605116, 7907913, 12000816, 26071011, 8825918, 23416954, 9467562, 8981969, 12788868, 9174404, 18063059, 19201392, 9111993, 26758973, 28946813, 27864651, 29420094, 31510104, 19258401, 12150334, 18062802, 30392857, 8099202, 7915166, 7595170, 8557249, 21765987, 14633923) (less)
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Pathogenic
(Dec 05, 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: SCV000776478.6
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 634 of the RET protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 634 of the RET protein (p.Cys634Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with medullary thyroid carcinoma or pheochromcytomas and multiple endocrine neoplasia type 2 (PMID: 8099202, 9111993, 9950371, 12000816, 12150334, 19201392, 21765987, 26230854, 26356818). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13908). 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. This variant disrupts the p.Cys634 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7824936, 8099202, 8103403, 8918855, 11939755, 12000816, 16865647, 21765987, 21810974, 24331334, 24716929, 26678667). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 03, 2023)
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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: SCV001174224.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.C634G pathogenic mutation (also known as c.1900T>G), located in coding exon 11 of the RET gene, results from a T to G substitution at … (more)
The p.C634G pathogenic mutation (also known as c.1900T>G), located in coding exon 11 of the RET gene, results from a T to G substitution at nucleotide position 1900. The cysteine at codon 634 is replaced by glycine, an amino acid with highly dissimilar properties. Amino acid position 634 is a well described mutation hot spot associated with Multiple Endocrine Neoplasia Type 2A (MEN2A) and Familial Medullary Thyroid Carcinoma (FMTC). This mutation has been reported in multiple MEN2A/FMTC families (Mulligan LM et al. Nature. 1993 Jun;363:458-60; Mulligan LM et al. Nat. Genet. 1994 Jan;6:70-4; McMahon R et al. Hum. Mol. Genet. 1994 Apr;3:643-6; Marsh DJ et al. Genomics. 1994 Sep;23:477-9; Mulligan LM et al. J. Intern. Med. 1995 Oct;238:343-6; Eng C et al. JAMA. 1996 Nov;276:1575-9). It has also been reported in individuals with MEN2A and Cutaneous Lichen Amyloidosis (Seri M et al. Clin. Genet. 1997 Feb;51:86-90; Scapineli JO et al. Fam. Cancer. 2016 10;15:625-33). Additionally, this mutation has been identified in multiple individuals with a history of pheochromocytoma (Seri M et al. Clin. Genet. 1997 Feb;51:86-90; Neumann HP et al. N. Engl. J. Med. 2002 May;346:1459-66; Algün E et al. J. Endocrinol. Invest. 2002 Jul-Aug;25:603-8; Amar L et al. J. Clin. Oncol. 2005 Dec;23:8812-8). The American Thyroid Association categorizes this mutation as high risk (ATA-H) and recommends surveillance, screening, and/or possible surgical interventions in early childhood (American Thyroid Association Guidelines Task Force. Thyroid. 2009 Jun;19:565-612; Wells SA et al. Thyroid. 2015 Jun;25:567-610). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown. (less)
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Pathogenic
(Dec 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV001144498.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
Comment:
Located at a critical residue of the protein. Not found in the total gnomAD dataset, and the data is high quality (0/278388 chr). Found in … (more)
Located at a critical residue of the protein. Not found in the total gnomAD dataset, and the data is high quality (0/278388 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Damaging to protein function(s) relevant to disease mechanism. Co-segregation with disease is reported. (less)
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Pathogenic
(Apr 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Familial medullary thyroid carcinoma
Affected status: yes
Allele origin:
germline
|
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499814.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Pathogenic
(Feb 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198056.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(May 09, 2002)
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no assertion criteria provided
Method: literature only
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MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035178.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 20, 2024 |
Comment on evidence:
In affected members of 3 families with MEN2A, Mulligan et al. (1993) found a TGC-to-GGC transversion at basepair 1831 of codon 380 in the RET … (more)
In affected members of 3 families with MEN2A, Mulligan et al. (1993) found a TGC-to-GGC transversion at basepair 1831 of codon 380 in the RET gene, resulting in substitution of glycine for cysteine (C380G; 164761.0003). (The codon numbered 380 on the basis of the partial RET sequence published by Takahashi et al. (1988) is numbered codon 634 on the basis of the full-length RET sequence (Mulligan et al., 1994).) Robinson et al. (1994) and Seri et al. (1997) likewise identified the C634G mutation in families with MEN2A associated with cutaneous lichen amyloidosis (PLCA; see 105250). In a 3-generation family with MEN2A, Chen et al. (2023) identified a germline C634G mutation in 4 family members. Three of them had been diagnosed with pheochromocytoma and medullary thyroid cancer, while the youngest, aged 18 years, had no evidence of disease. In a patient and her father with pheochromocytoma (171300), Eng et al. (1995) identified a germline C634G mutation. Neumann et al. (2002) identified the C634G substitution in the germline of a patient with pheochromocytoma. The mutation was not identified in 600 control chromosomes. (less)
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Pathogenic
(May 09, 2002)
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no assertion criteria provided
Method: literature only
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PHEOCHROMOCYTOMA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035179.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 20, 2024 |
Comment on evidence:
In affected members of 3 families with MEN2A, Mulligan et al. (1993) found a TGC-to-GGC transversion at basepair 1831 of codon 380 in the RET … (more)
In affected members of 3 families with MEN2A, Mulligan et al. (1993) found a TGC-to-GGC transversion at basepair 1831 of codon 380 in the RET gene, resulting in substitution of glycine for cysteine (C380G; 164761.0003). (The codon numbered 380 on the basis of the partial RET sequence published by Takahashi et al. (1988) is numbered codon 634 on the basis of the full-length RET sequence (Mulligan et al., 1994).) Robinson et al. (1994) and Seri et al. (1997) likewise identified the C634G mutation in families with MEN2A associated with cutaneous lichen amyloidosis (PLCA; see 105250). In a 3-generation family with MEN2A, Chen et al. (2023) identified a germline C634G mutation in 4 family members. Three of them had been diagnosed with pheochromocytoma and medullary thyroid cancer, while the youngest, aged 18 years, had no evidence of disease. In a patient and her father with pheochromocytoma (171300), Eng et al. (1995) identified a germline C634G mutation. Neumann et al. (2002) identified the C634G substitution in the germline of a patient with pheochromocytoma. The mutation was not identified in 600 control chromosomes. (less)
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Citation text
Robinson, M. F., Cote, G. J., Nunziata, V., Brandi, M. L., Ferrer, J. P., Martins Bugalho, M. J. G., Almeida Ruas, M. M., Chik, C., Colantuoni, V., Gagel, R. F. Mutation of a specific codon of the RET proto-oncogene in the multiple endocrine neoplasia type 2A/cutaneous lichen amyloidosis syndrome. (Abstract) Fifth International Workshop on Multiple Endocrine Neoplasia, Stockholm, Archipelago 1994.
Citation text
Robinson, M. F., Cote, G. J., Nunziata, V., Brandi, M. L., Ferrer, J. P., Martins Bugalho, M. J. G., Almeida Ruas, M. M., Chik, C., Colantuoni, V., Gagel, R. F. Mutation of a specific codon of the RET proto-oncogene in the multiple endocrine neoplasia type 2A/cutaneous lichen amyloidosis syndrome. (Abstract) Fifth International Workshop on Multiple Endocrine Neoplasia, Stockholm, Archipelago 1994.
Comment:
The RET c.1900T>G;p.Cys634Gly variant (rs75076352) has been published in multiple individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (FMTC) and at least one individual with pheochromocytoma (American Thyroid Association Guidelines Task Force 2009, Hedayati 2011, Neumann 2002, Wells 2015). The variant is listed in the ClinVar database (Variation ID: 13908), but is not listed in the Genome Aggregation Database. The cysteine at codon 634 is conserved across a variety of species and computational programs (PolyPhen2, SIFT) predict this variant is deleterious to protein function. Considering available information, this variant is classified as pathogenic. References: American Thyroid Association Guidelines Task Force. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 19(6):565-612. 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. 2011:264248. Neumann HP et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002 346(19):1459-66. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610.
Comment:
Variant summary: RET c.1900T>G (p.Cys634Gly) 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 most frequent mutations in the RET proto-oncogene have been found in five cysteine codons 609, 611, 618, and 620 of exon 10 and codon 634 of exon 11. The variant was absent in 247534 control chromosomes. c.1900T>G has been widely reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Phaeochromocytoma/Medullary Carcinoma of the Thyroid/ multiple endocrine neoplasia type 2A (MEN 2A)-cutaneous lichen amyloidosis (example, Mulligan_1993, Neumann_2002, Sanz_2009, Hedayati_2011, Qi_2018, Maciel_2019). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed 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: 24466223, 26267327, 30763276, 27349013, 28605116, 7907913, 12000816, 26071011, 8825918, 23416954, 9467562, 8981969, 12788868, 9174404, 18063059, 19201392, 9111993, 26758973, 28946813, 27864651, 29420094, 31510104, 19258401, 12150334, 18062802, 30392857, 8099202, 7915166, 7595170, 8557249, 21765987, 14633923)
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 634 of the RET protein (p.Cys634Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with medullary thyroid carcinoma or pheochromcytomas and multiple endocrine neoplasia type 2 (PMID: 8099202, 9111993, 9950371, 12000816, 12150334, 19201392, 21765987, 26230854, 26356818). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13908). 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. This variant disrupts the p.Cys634 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7824936, 8099202, 8103403, 8918855, 11939755, 12000816, 16865647, 21765987, 21810974, 24331334, 24716929, 26678667). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.C634G pathogenic mutation (also known as c.1900T>G), located in coding exon 11 of the RET gene, results from a T to G substitution at nucleotide position 1900. The cysteine at codon 634 is replaced by glycine, an amino acid with highly dissimilar properties. Amino acid position 634 is a well described mutation hot spot associated with Multiple Endocrine Neoplasia Type 2A (MEN2A) and Familial Medullary Thyroid Carcinoma (FMTC). This mutation has been reported in multiple MEN2A/FMTC families (Mulligan LM et al. Nature. 1993 Jun;363:458-60; Mulligan LM et al. Nat. Genet. 1994 Jan;6:70-4; McMahon R et al. Hum. Mol. Genet. 1994 Apr;3:643-6; Marsh DJ et al. Genomics. 1994 Sep;23:477-9; Mulligan LM et al. J. Intern. Med. 1995 Oct;238:343-6; Eng C et al. JAMA. 1996 Nov;276:1575-9). It has also been reported in individuals with MEN2A and Cutaneous Lichen Amyloidosis (Seri M et al. Clin. Genet. 1997 Feb;51:86-90; Scapineli JO et al. Fam. Cancer. 2016 10;15:625-33). Additionally, this mutation has been identified in multiple individuals with a history of pheochromocytoma (Seri M et al. Clin. Genet. 1997 Feb;51:86-90; Neumann HP et al. N. Engl. J. Med. 2002 May;346:1459-66; Algün E et al. J. Endocrinol. Invest. 2002 Jul-Aug;25:603-8; Amar L et al. J. Clin. Oncol. 2005 Dec;23:8812-8). The American Thyroid Association categorizes this mutation as high risk (ATA-H) and recommends surveillance, screening, and/or possible surgical interventions in early childhood (American Thyroid Association Guidelines Task Force. Thyroid. 2009 Jun;19:565-612; Wells SA et al. Thyroid. 2015 Jun;25:567-610). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.
Comment:
Located at a critical residue of the protein. Not found in the total gnomAD dataset, and the data is high quality (0/278388 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Damaging to protein function(s) relevant to disease mechanism. Co-segregation with disease is reported.
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. |
Comment:
The RET c.1900T>G;p.Cys634Gly variant (rs75076352) has been published in multiple individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (FMTC) and at least one individual with pheochromocytoma (American Thyroid Association Guidelines Task Force 2009, Hedayati 2011, Neumann 2002, Wells 2015). The variant is listed in the ClinVar database (Variation ID: 13908), but is not listed in the Genome Aggregation Database. The cysteine at codon 634 is conserved across a variety of species and computational programs (PolyPhen2, SIFT) predict this variant is deleterious to protein function. Considering available information, this variant is classified as pathogenic. References: American Thyroid Association Guidelines Task Force. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 19(6):565-612. 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. 2011:264248. Neumann HP et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002 346(19):1459-66. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610.
Comment:
Variant summary: RET c.1900T>G (p.Cys634Gly) 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 most frequent mutations in the RET proto-oncogene have been found in five cysteine codons 609, 611, 618, and 620 of exon 10 and codon 634 of exon 11. The variant was absent in 247534 control chromosomes. c.1900T>G has been widely reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Phaeochromocytoma/Medullary Carcinoma of the Thyroid/ multiple endocrine neoplasia type 2A (MEN 2A)-cutaneous lichen amyloidosis (example, Mulligan_1993, Neumann_2002, Sanz_2009, Hedayati_2011, Qi_2018, Maciel_2019). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed 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: 24466223, 26267327, 30763276, 27349013, 28605116, 7907913, 12000816, 26071011, 8825918, 23416954, 9467562, 8981969, 12788868, 9174404, 18063059, 19201392, 9111993, 26758973, 28946813, 27864651, 29420094, 31510104, 19258401, 12150334, 18062802, 30392857, 8099202, 7915166, 7595170, 8557249, 21765987, 14633923)
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 634 of the RET protein (p.Cys634Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with medullary thyroid carcinoma or pheochromcytomas and multiple endocrine neoplasia type 2 (PMID: 8099202, 9111993, 9950371, 12000816, 12150334, 19201392, 21765987, 26230854, 26356818). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13908). 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. This variant disrupts the p.Cys634 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7824936, 8099202, 8103403, 8918855, 11939755, 12000816, 16865647, 21765987, 21810974, 24331334, 24716929, 26678667). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.C634G pathogenic mutation (also known as c.1900T>G), located in coding exon 11 of the RET gene, results from a T to G substitution at nucleotide position 1900. The cysteine at codon 634 is replaced by glycine, an amino acid with highly dissimilar properties. Amino acid position 634 is a well described mutation hot spot associated with Multiple Endocrine Neoplasia Type 2A (MEN2A) and Familial Medullary Thyroid Carcinoma (FMTC). This mutation has been reported in multiple MEN2A/FMTC families (Mulligan LM et al. Nature. 1993 Jun;363:458-60; Mulligan LM et al. Nat. Genet. 1994 Jan;6:70-4; McMahon R et al. Hum. Mol. Genet. 1994 Apr;3:643-6; Marsh DJ et al. Genomics. 1994 Sep;23:477-9; Mulligan LM et al. J. Intern. Med. 1995 Oct;238:343-6; Eng C et al. JAMA. 1996 Nov;276:1575-9). It has also been reported in individuals with MEN2A and Cutaneous Lichen Amyloidosis (Seri M et al. Clin. Genet. 1997 Feb;51:86-90; Scapineli JO et al. Fam. Cancer. 2016 10;15:625-33). Additionally, this mutation has been identified in multiple individuals with a history of pheochromocytoma (Seri M et al. Clin. Genet. 1997 Feb;51:86-90; Neumann HP et al. N. Engl. J. Med. 2002 May;346:1459-66; Algün E et al. J. Endocrinol. Invest. 2002 Jul-Aug;25:603-8; Amar L et al. J. Clin. Oncol. 2005 Dec;23:8812-8). The American Thyroid Association categorizes this mutation as high risk (ATA-H) and recommends surveillance, screening, and/or possible surgical interventions in early childhood (American Thyroid Association Guidelines Task Force. Thyroid. 2009 Jun;19:565-612; Wells SA et al. Thyroid. 2015 Jun;25:567-610). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.
Comment:
Located at a critical residue of the protein. Not found in the total gnomAD dataset, and the data is high quality (0/278388 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Damaging to protein function(s) relevant to disease mechanism. Co-segregation with disease is reported.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A Familial Case of Multiple Endocrine Neoplasia 2A: From Morphology to Genetic Alterations Penetration in Three Generations of a Family. | Chen L | Diagnostics (Basel, Switzerland) | 2023 | PMID: 36900098 |
| Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study. | Maciel RMB | Endocrine connections | 2019 | PMID: 30763276 |
| Genetic characterization of medullary thyroid cancer in childhood survivors of the Chernobyl accident. | Fisher SB | Surgery | 2019 | PMID: 30392857 |
| Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors. | La Pietra V | European journal of medicinal chemistry | 2018 | PMID: 29549836 |
| The Clinical Spectrum of Multiple Endocrine Neoplasia Type 2A with Cutaneous Lichen Amyloidosis in Ethnic Han Chinese. | Qi XP | Cancer investigation | 2018 | PMID: 29420094 |
| Detection of early stage medullary thyroid carcinoma by measuring serum calcitonin using an electro chemiluminescence immuno-assay: A case report of a young Japanese woman with a high-risk RET mutation. | Abe Y | Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology | 2017 | PMID: 29026273 |
| MEN 2A-related cutaneous lichen amyloidosis: report of three kindred and systematic literature review of clinical, biochemical and molecular characteristics. | Scapineli JO | Familial cancer | 2016 | PMID: 26920351 |
| Diversity of mutations in the RET proto-oncogene and its oncogenic mechanism in medullary thyroid cancer. | Hedayati M | Critical reviews in clinical laboratory sciences | 2016 | PMID: 26678667 |
| RET mutation p.S891A in a Chinese family with familial medullary thyroid carcinoma and associated cutaneous amyloidosis binding OSMR variant p.G513D. | Qi XP | Oncotarget | 2015 | PMID: 26356818 |
| Bioinformatic Challenges in Clinical Diagnostic Application of Targeted Next Generation Sequencing: Experience from Pheochromocytoma. | Crona J | PloS one | 2015 | PMID: 26230854 |
| 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 |
| Characterization of wild-type and mutated RET proto- oncogene associated with familial medullary thyroid cancer. | Masbi MH | Asian Pacific journal of cancer prevention : APJCP | 2014 | PMID: 24716929 |
| Multiple endocrine neoplasia type 2A: case report. | Păun DL | Chirurgia (Bucharest, Romania : 1990) | 2013 | PMID: 24331334 |
| In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. | Cosci B | Endocrine-related cancer | 2011 | PMID: 21810974 |
| 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 |
| 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 |
| 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 |
| Multiple endocrine neoplasia type 2a and germ line C634G RET mutation diagnosed in an 80-year-old patient. | Sanz C | Annales d'endocrinologie | 2009 | PMID: 19201392 |
| Familial prevalence and age of RET germline mutations: implications for screening. | Machens A | Clinical endocrinology | 2008 | PMID: 18062802 |
| Pheochromocytoma penetrance varies by RET mutation in MEN 2A. | Quayle FJ | Surgery | 2007 | PMID: 18063059 |
| 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 |
| Change in the spectrum of RET mutations diagnosed between 1994 and 2006. | Frank-Raue K | Clinical laboratory | 2007 | PMID: 17605401 |
| RET proto-oncogene genotyping using unlabeled probes, the masking technique, and amplicon high-resolution melting analysis. | Margraf RL | The Journal of molecular diagnostics : JMD | 2007 | PMID: 17384210 |
| Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype. | Frank-Raue K | European journal of endocrinology | 2006 | PMID: 16868135 |
| Genotype-phenotype correlations in Hungarian patients with hereditary medullary thyroid cancer. | Patocs A | Wiener klinische Wochenschrift | 2006 | PMID: 16865647 |
| Hereditary medullary thyroid cancer in Slovenia--genotype-phenotype correlations. | Bergant D | Wiener klinische Wochenschrift | 2006 | PMID: 16865646 |
| RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. | de Groot JW | Endocrine reviews | 2006 | PMID: 16849421 |
| Impact of RET proto-oncogene analysis on the clinical management of multiple endocrine neoplasia type 2. | Toledo SP | Clinics (Sao Paulo, Brazil) | 2006 | PMID: 16532227 |
| Genetic testing in pheochromocytoma or functional paraganglioma. | Amar L | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2005 | PMID: 16314641 |
| Clinical characteristics and genetic screening of an extended family with MEN2A. | Algün E | Journal of endocrinological investigation | 2002 | PMID: 12150334 |
| Germ-line mutations in nonsyndromic pheochromocytoma. | Neumann HP | The New England journal of medicine | 2002 | PMID: 12000816 |
| Early onset of medullary thyroid carcinoma in a kindred with multiple endocrine neoplasia type iia associated with cutaneous lichen amyloidosis. | Lemos MC | Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists | 2002 | PMID: 11939755 |
| Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties. | Machens A | The Journal of clinical endocrinology and metabolism | 2001 | PMID: 11238493 |
| High prevalence of the C634Y mutation in the RET proto-oncogene in MEN 2A families in Spain. | Sánchez B | Journal of medical genetics | 1999 | PMID: 9950371 |
| Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D'etude des Tumeurs à Calcitonine. | Schuffenecker I | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9467562 |
| 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 |
| A Cys634Gly substitution of the RET proto-oncogene in a family with recurrence of multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis. | Seri M | Clinical genetics | 1997 | PMID: 9111993 |
| 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 |
| Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. "Study Group Multiple Endocrine Neoplasia Austria (SMENA)". | Fink M | International journal of cancer | 1996 | PMID: 8797874 |
| Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. | Santoro M | Science (New York, N.Y.) | 1995 | PMID: 7824936 |
| Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. | Mulligan LM | Journal of internal medicine | 1995 | PMID: 7595170 |
| Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma. | Eng C | Genes, chromosomes & cancer | 1995 | PMID: 7536460 |
| Direct, non-radioactive detection of mutations in multiple endocrine neoplasia type 2A families. | McMahon R | Human molecular genetics | 1994 | PMID: 7915166 |
| Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. | Mulligan LM | Nature genetics | 1994 | PMID: 7907913 |
| A rapid screening method for the detection of mutations in the RET proto-oncogene in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma families. | Marsh DJ | Genomics | 1994 | PMID: 7835899 |
| Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. | Donis-Keller H | Human molecular genetics | 1993 | PMID: 8103403 |
| Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. | Mulligan LM | Nature | 1993 | PMID: 8099202 |
| Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. | Takahashi M | Oncogene | 1988 | PMID: 3078962 |
| Robinson, M. F., Cote, G. J., Nunziata, V., Brandi, M. L., Ferrer, J. P., Martins Bugalho, M. J. G., Almeida Ruas, M. M., Chik, C., Colantuoni, V., Gagel, R. F. Mutation of a specific codon of the RET proto-oncogene in the multiple endocrine neoplasia type 2A/cutaneous lichen amyloidosis syndrome. (Abstract) Fifth International Workshop on Multiple Endocrine Neoplasia, Stockholm, Archipelago 1994. | - | - | - | - |
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Text-mined citations for rs75076352 ...
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Record last updated Sep 29, 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.