The RET c.1901G>A;p.Cys634Tyr variant (rs75996173) is reported in the literature in multiple individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (American Thyroid Association Guidelines Task Force 2009, Punales 2003, Wells 2015). This variant is found on a single chromosome in the Genome Aggregation Database (1/247574 alleles), indicating it is not a common polymorphism. The cysteine at codon 634 is highly conserved, and other amino acid substitutions at this codon (Arg, Gly, Phe, Ser, Trp) are considered causative for MEN2A (Wells 2015). Functional characterization of the p.Cys364Tyr variant and other missense variants at the same codon (p.Cys634Arg, p.Cys634Trp) indicates increased auto-phosphorylation and activation of downstream targets (Santoro 1995), resulting in enhanced malignant transformation of cells (Cosci 2011, Santoro 1995). Based on available information, the p.Cys634Tyr variant is considered to be pathogenic. References: American Thyroid Association Guidelines Task Force et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 Jun;19(6):565-612. Cosci B et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer. 2011 Sep 20;18(5):603-12. Punales MK et al. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003 Jun;88(6):2644-9. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995 Jan 20;267(5196):381-3. Wells S et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610.
ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.1901G>A (p.Cys634Tyr)
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.
(30)
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
30
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_020975.6(RET):c.1901G>A (p.Cys634Tyr)
Variation ID: 13909 Accession: VCV000013909.38
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q11.21 10: 43114501 (GRCh38) [ NCBI UCSC ] 10: 43609949 (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 Apr 4, 2013 Oct 26, 2024 Mar 26, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.1901G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Cys634Tyr missense NM_000323.2:c.1901G>A NP_000314.1:p.Cys634Tyr missense NM_001355216.2:c.1139G>A NP_001342145.1:p.Cys380Tyr missense NM_001406743.1:c.1901G>A NP_001393672.1:p.Cys634Tyr missense NM_001406744.1:c.1901G>A NP_001393673.1:p.Cys634Tyr missense NM_001406759.1:c.1901G>A NP_001393688.1:p.Cys634Tyr missense NM_001406760.1:c.1901G>A NP_001393689.1:p.Cys634Tyr missense NM_001406761.1:c.1772G>A NP_001393690.1:p.Cys591Tyr missense NM_001406762.1:c.1772G>A NP_001393691.1:p.Cys591Tyr missense NM_001406764.1:c.1772G>A NP_001393693.1:p.Cys591Tyr missense NM_001406766.1:c.1613G>A NP_001393695.1:p.Cys538Tyr missense NM_001406767.1:c.1613G>A NP_001393696.1:p.Cys538Tyr missense NM_001406769.1:c.1505G>A NP_001393698.1:p.Cys502Tyr missense NM_001406770.1:c.1613G>A NP_001393699.1:p.Cys538Tyr missense NM_001406771.1:c.1463G>A NP_001393700.1:p.Cys488Tyr missense NM_001406772.1:c.1505G>A NP_001393701.1:p.Cys502Tyr missense NM_001406773.1:c.1463G>A NP_001393702.1:p.Cys488Tyr missense NM_001406774.1:c.1376G>A NP_001393703.1:p.Cys459Tyr missense NM_001406775.1:c.1175G>A NP_001393704.1:p.Cys392Tyr missense NM_001406776.1:c.1175G>A NP_001393705.1:p.Cys392Tyr missense NM_001406777.1:c.1175G>A NP_001393706.1:p.Cys392Tyr missense NM_001406778.1:c.1175G>A NP_001393707.1:p.Cys392Tyr missense NM_001406779.1:c.1004G>A NP_001393708.1:p.Cys335Tyr missense NM_001406780.1:c.1004G>A NP_001393709.1:p.Cys335Tyr missense NM_001406781.1:c.1004G>A NP_001393710.1:p.Cys335Tyr missense NM_001406782.1:c.1004G>A NP_001393711.1:p.Cys335Tyr missense NM_001406783.1:c.875G>A NP_001393712.1:p.Cys292Tyr missense NM_001406784.1:c.911G>A NP_001393713.1:p.Cys304Tyr missense NM_001406785.1:c.884G>A NP_001393714.1:p.Cys295Tyr missense NM_001406786.1:c.875G>A NP_001393715.1:p.Cys292Tyr missense NM_001406788.1:c.716G>A NP_001393717.1:p.Cys239Tyr missense NM_001406789.1:c.716G>A NP_001393718.1:p.Cys239Tyr missense NM_001406790.1:c.716G>A NP_001393719.1:p.Cys239Tyr missense NM_001406791.1:c.596G>A NP_001393720.1:p.Cys199Tyr missense NM_001406792.1:c.452G>A NP_001393721.1:p.Cys151Tyr missense NM_001406793.1:c.452G>A NP_001393722.1:p.Cys151Tyr missense NM_001406794.1:c.452G>A NP_001393723.1:p.Cys151Tyr missense NM_020629.2:c.1901G>A NP_065680.1:p.Cys634Tyr missense NM_020630.7:c.1901G>A NP_065681.1:p.Cys634Tyr missense NC_000010.11:g.43114501G>A NC_000010.10:g.43609949G>A NG_007489.1:g.42433G>A LRG_518:g.42433G>A LRG_518t1:c.1901G>A LRG_518p1:p.Cys634Tyr LRG_518t2:c.1901G>A LRG_518p2:p.Cys634Tyr P07949:p.Cys634Tyr - Protein change
- C634Y, C380Y, C292Y, C392Y, C502Y, C538Y, C239Y, C335Y, C459Y, C591Y, C199Y, C304Y, C488Y, C151Y, C295Y
- Other names
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p.C634Y:TGC>TAC
- Canonical SPDI
- NC_000010.11:43114500: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.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- 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. |
|||
| RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3598 | 3720 | |
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 (2) |
no assertion criteria provided
|
Oct 6, 2021 | RCV000014925.34 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
May 21, 2023 | RCV000014924.38 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 6, 2022 | RCV000129490.15 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 24, 2023 | RCV000182582.27 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 13, 2016 | RCV000422622.9 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 7, 2023 | RCV000425364.14 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000421191.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 13, 2016 | RCV000438527.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 13, 2016 | RCV000432822.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 4, 2024 | RCV000476408.19 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 26, 2024 | RCV003989285.3 | |
|
RET-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jun 24, 2024 | RCV004739307.1 |
| click to load more click to collapse | ||||
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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|---|---|---|---|---|---|
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Pathogenic
(Oct 29, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605016.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 08, 2022 |
Comment:
The RET c.1901G>A;p.Cys634Tyr variant (rs75996173) is reported in the literature in multiple individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary … (more)
The RET c.1901G>A;p.Cys634Tyr variant (rs75996173) is reported in the literature in multiple individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (American Thyroid Association Guidelines Task Force 2009, Punales 2003, Wells 2015). This variant is found on a single chromosome in the Genome Aggregation Database (1/247574 alleles), indicating it is not a common polymorphism. The cysteine at codon 634 is highly conserved, and other amino acid substitutions at this codon (Arg, Gly, Phe, Ser, Trp) are considered causative for MEN2A (Wells 2015). Functional characterization of the p.Cys364Tyr variant and other missense variants at the same codon (p.Cys634Arg, p.Cys634Trp) indicates increased auto-phosphorylation and activation of downstream targets (Santoro 1995), resulting in enhanced malignant transformation of cells (Cosci 2011, Santoro 1995). Based on available information, the p.Cys634Tyr variant is considered to be pathogenic. References: American Thyroid Association Guidelines Task Force et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 Jun;19(6):565-612. Cosci B et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer. 2011 Sep 20;18(5):603-12. Punales MK et al. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003 Jun;88(6):2644-9. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995 Jan 20;267(5196):381-3. 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
(Sep 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579279.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS1, PS4, PM1, PM2_SUP, PP3, PP4
|
Number of individuals with the variant: 1
Sex: female
|
|
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Pathogenic
(May 14, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002047250.3
First in ClinVar: Jan 01, 2022 Last updated: Jan 06, 2024 |
Comment:
The RET c.1901G>A (p.Cys634Tyr) variant has been reported in the published literature in multiple individuals with MEN2A and/or FMTC (PMID: 7835899 (1994), 9950371 (1999), 12000816 … (more)
The RET c.1901G>A (p.Cys634Tyr) variant has been reported in the published literature in multiple individuals with MEN2A and/or FMTC (PMID: 7835899 (1994), 9950371 (1999), 12000816 (2002), 21765987 (2011), 25810047 (2015), 26732158 (2016), 28099363 (2017), 33167350 (2020)). A functional study found the variant has a damaging effect on RET function (PMID: 7824936 (2015)). The frequency of this variant in the general population, 0.000004 (1/247574 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Dec 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hirschsprung disease, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005054215.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
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Pathogenic
(May 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005382535.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Comment:
The observed missense c.1901G>A (p.Cys634Tyr) variant in RET gene has been reported in multiple individuals affected with RET-related disorders (Chiefari et al., 1998; Sánchez et … (more)
The observed missense c.1901G>A (p.Cys634Tyr) variant in RET gene has been reported in multiple individuals affected with RET-related disorders (Chiefari et al., 1998; Sánchez et al., 1999; Jackson et al., 2005; Valente et al., 2013; Valdés et al., 2015). It has also been observed to segregate with disease in related individuals (Valente et al., 2013). Amino acid position 634 is a well described mutation hot spot associated with Multiple endocrine neoplasia type 2A (MEN2A). Functional characterization of the p.Cys634Tyr variant and other missense variants at the same amino acid position (p.Cys634Arg, p.Cys634Trp) indicated increased auto-phosphorylation and activation of downstream targets, resulting in enhanced malignant transformation of cells (Cosci et al., 2011, Santoro et al., 1995). This variant is present with allele frequency of 0.0004% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic/ Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Cys634Tyr in RET is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 634 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the endocrine system (present)
|
|
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Pathogenic
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782257.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
|
|
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Pathogenic
(Aug 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785514.2
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
|
|
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Pathogenic
(Jul 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2a
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053074.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 22, 2020 |
Comment:
Variant summary: RET c.1901G>A (p.Cys634Tyr) results in a non-conservative amino acid change located in the extracellular domain of the encoded protein sequence. Five of five … (more)
Variant summary: RET c.1901G>A (p.Cys634Tyr) results in a non-conservative amino acid change located in the extracellular domain of 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 247574 control chromosomes. c.1901G>A has been well reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2A (example Chiefari_1998, Frank-Raue_2006). These data indicate that the variant is strongly associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating a gain of function mechanism due to activation of the RET proto-oncogene (example Santoro_1995). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2B
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Suma Genomics
Accession: SCV001847694.1
First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021 |
|
|
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Pathogenic
(May 14, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000842752.3
First in ClinVar: Dec 06, 2016 Last updated: Dec 31, 2022 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been … (more)
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. The American Thyroid Association has placed this variant into the ATA-H category, formerly known as level C, for having a high risk of developing aggressive medullary thyroid carcinoma (MTC; see PMID: 25810047). This variant segregates with disease in multiple families. Computational tools predict that this variant is damaging. (less)
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Pathogenic
(Mar 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000234934.10
First in ClinVar: Jul 05, 2015 Last updated: Apr 01, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: high transforming ability, constitutive kinase activation (Santoro 1995, Ito 1997); In silico analysis supports that this missense variant … (more)
Published functional studies demonstrate a damaging effect: high transforming ability, constitutive kinase activation (Santoro 1995, Ito 1997); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(Cys380Tyr); This variant is associated with the following publications: (PMID: 12711285, 8797874, 9146685, 23723040, 19062722, 27558615, 25515555, 26254625, 29133048, 29656518, 23330657, 7835899, 21765987, 7824936, 8099202, 15858153, 8626834, 21054478, 16314641, 17895320, 24716929, 12000816, 7874109, 20080836, 26732158, 28099363, 26758973, 26572832, 26876062, 27539324, 23868299, 11987030, 30139385, 29197744, 7881414, 9230192, 28469506, 30113649, 21655256, 18063059, 12686527, 9950371, 7860065, 16099853, 11524247, 19240193, 7914213, 7491519, 12604374, 9820617, 9699127, 31062739, 30122763, 16158949, 20516206, 29625052, 31510104, 32989896, 8909322, 18096130, 9497883, 8984233, 35627249, 28152038, 30763276, 9706252, 25545346, 33340421, 33219105, 35418818, 14633923) (less)
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Pathogenic
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2B
Affected status: yes
Allele origin:
unknown
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004015290.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
The family RET mutation (C634Y) was detected in this blood specimen. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which … (more)
The family RET mutation (C634Y) was detected in this blood specimen. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 634 of the RET protein (p.Cys634Tyr). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A and medullary thyroid cancer and pheochromocytoma (PMID: 2008030, 8099202, 12000816, 23723040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13909) with 22 submissions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RET function (PMID: 7824936). 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: 8099202, 12000816, 21765987). Therefore, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004018493.1
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, 21834681]. 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, 21834681]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26732158, 17188172, 34439168, 20801952, 33827484, 25810047]. (less)
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Pathogenic
(May 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)
Accession: SCV003930402.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Number of individuals with the variant: 2
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|
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Pathogenic
(Feb 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002522517.2
First in ClinVar: Jun 05, 2022 Last updated: Jan 26, 2024 |
Number of individuals with the variant: 3
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Pathogenic
(Jan 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000543790.8
First in ClinVar: Apr 17, 2017 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 634 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 634 of the RET protein (p.Cys634Tyr). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A and medullary thyroid cancer and pheochromocytoma (PMID: 2008030, 8099202, 12000816, 23723040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13909). 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. Experimental studies have shown that this missense change affects RET function (PMID: 7824936). 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: 8099202, 12000816, 21765987). 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 26, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Hirschsprung disease, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807294.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jun 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184262.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.C634Y pathogenic mutation (also known as c.1901G>A) is located in coding exon 11 of the RET gene. This alteration results from a G to … (more)
The p.C634Y pathogenic mutation (also known as c.1901G>A) is located in coding exon 11 of the RET gene. This alteration results from a G to A substitution at nucleotide position 1901. The cysteine at codon 634 is replaced by tyrosine, an amino acid with highly dissimilar properties. The p.C634Y mutation has been reported in several unrelated families diagnosed with MEN2A and/or familial medullary thyroid carcinoma (FMTC) (Mulligan et al. Nature. 1993;363:458-460; Marsh DJ et al. Genomics. 1994;23(2):477-479; Hedayati et al. J Thyroid Res. 2011;2011:264248; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122). Amino acid position 634 is a well described mutation hot spot associated with MEN2A/FMTC. Studies evaluating genotype-phenotype correlation suggest higher penetrance for pheochromocytoma in MEN2 patients with mutations at amino acid position 634 (Neumann HP et al. N. Engl. J. Med. 2002;346:1459-66, Quayle FJ et al. Surgery 2007;142:800-5; Yip L et al. Arch Surg 2003;138:409-16). Revised American Thyroid Association Guidelines categorize the p.C634Y alteration as high risk (ATA-H) and recommend surveillance and prophylactic surgery in early childhood (Wells SA et al. Thyroid 2015 Jun;25(6):567-610). Of note, this alteration has been referred to as p.C380Y (c.1832G>A) and p.C634Y (c.2096G>A) in the published literature. Based on the available evidence, p.C634Y is classified as a pathogenic mutation. (less)
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Pathogenic
(May 09, 2002)
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no assertion criteria provided
Method: literature only
|
MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035180.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected members of 2 families with MEN2A, Mulligan et al. (1993) found a TGC-to-TAC transition at basepair 1832 of codon 380 resulting in substitution … (more)
In affected members of 2 families with MEN2A, Mulligan et al. (1993) found a TGC-to-TAC transition at basepair 1832 of codon 380 resulting in substitution of cysteine to tyrosine (CYS380TYR). (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).) Ceccherini et al. (1994) found the cys634-to-tyr (C634Y) mutation in a family with MEN2A associated with primary localized cutaneous lichen amyloidosis (PLCA; see 105250). Santoro et al. (1995) showed that this mutation is a transforming gene in NIH 3T3 cells as a consequence of constitutive activation of the RET kinase. In MEN2A and familial medullary thyroid carcinoma, point mutations result in the substitution of 1 of the 5 cysteine residues in the extracellular domain of RET. This causes RET dimerization at steady state. Neumann et al. (2002) identified the C634Y substitution in the germlines of 3 unrelated patients with sporadic pheochromocytoma (171300). The mutation was not identified in 600 control chromosomes. (less)
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Pathogenic
(May 09, 2002)
|
no assertion criteria provided
Method: literature only
|
PHEOCHROMOCYTOMA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035181.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected members of 2 families with MEN2A, Mulligan et al. (1993) found a TGC-to-TAC transition at basepair 1832 of codon 380 resulting in substitution … (more)
In affected members of 2 families with MEN2A, Mulligan et al. (1993) found a TGC-to-TAC transition at basepair 1832 of codon 380 resulting in substitution of cysteine to tyrosine (CYS380TYR). (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).) Ceccherini et al. (1994) found the cys634-to-tyr (C634Y) mutation in a family with MEN2A associated with primary localized cutaneous lichen amyloidosis (PLCA; see 105250). Santoro et al. (1995) showed that this mutation is a transforming gene in NIH 3T3 cells as a consequence of constitutive activation of the RET kinase. In MEN2A and familial medullary thyroid carcinoma, point mutations result in the substitution of 1 of the 5 cysteine residues in the extracellular domain of RET. This causes RET dimerization at steady state. Neumann et al. (2002) identified the C634Y substitution in the germlines of 3 unrelated patients with sporadic pheochromocytoma (171300). The mutation was not identified in 600 control chromosomes. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926394.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(Oct 06, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Pheochromocytoma
Affected status: no
Allele origin:
maternal
|
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University
Accession: SCV002028352.1
First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021 |
Number of individuals with the variant: 3
Age: 5-65 years
Sex: mixed
Ethnicity/Population group: Chinese
Geographic origin: China
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Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
Neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000505641.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
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Likely pathogenic
(May 13, 2016)
|
no assertion criteria provided
Method: literature only
|
Multiple endocrine neoplasia, type 1
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000510493.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
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Likely pathogenic
(May 13, 2016)
|
no assertion criteria provided
Method: literature only
|
Multiple endocrine neoplasia type 2B
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000510496.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 13, 2016)
|
no assertion criteria provided
Method: literature only
|
Medullary thyroid carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000510492.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
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Likely pathogenic
(May 13, 2016)
|
no assertion criteria provided
Method: literature only
|
Multiple endocrine neoplasia type 4
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000510494.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 13, 2016)
|
no assertion criteria provided
Method: literature only
|
Multiple endocrine neoplasia type 2A
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000510495.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958702.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Jun 24, 2024)
|
no assertion criteria provided
Method: clinical testing
|
RET-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005361904.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The RET c.1901G>A variant is predicted to result in the amino acid substitution p.Cys634Tyr. This variant has been reported in multiple individuals with MEN2A, medullary … (more)
The RET c.1901G>A variant is predicted to result in the amino acid substitution p.Cys634Tyr. This variant has been reported in multiple individuals with MEN2A, medullary thyroid cancer, and pheochromocytoma (Mulligan et al. 1993. PubMed ID: 8099202; Sanchez et al. 1999. PubMed ID: 9950371; Toledo et al. 2010. PubMed ID: 20080836). Functional studies have shown this variant and other amino acid changes at this position result in increased auto-phosphorylation and activation of downstream targets which enhances malignant transformation of cells (Santoro M et al. 1995. PubMed ID: 7824936; Cosci B et al. 2011. PubMed ID: 21810974). This variant is present in one individual in the gnomAD database. This variant is classified as pathogenic in ClinVar with multiple submitters in agreement (https://www.ncbi.nlm.nih.gov/clinvar/variation/13909/). We interpret this variant to be pathogenic. (less)
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Comment:
Comment:
The RET c.1901G>A (p.Cys634Tyr) variant has been reported in the published literature in multiple individuals with MEN2A and/or FMTC (PMID: 7835899 (1994), 9950371 (1999), 12000816 (2002), 21765987 (2011), 25810047 (2015), 26732158 (2016), 28099363 (2017), 33167350 (2020)). A functional study found the variant has a damaging effect on RET function (PMID: 7824936 (2015)). The frequency of this variant in the general population, 0.000004 (1/247574 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Comment:
The observed missense c.1901G>A (p.Cys634Tyr) variant in RET gene has been reported in multiple individuals affected with RET-related disorders (Chiefari et al., 1998; Sánchez et al., 1999; Jackson et al., 2005; Valente et al., 2013; Valdés et al., 2015). It has also been observed to segregate with disease in related individuals (Valente et al., 2013). Amino acid position 634 is a well described mutation hot spot associated with Multiple endocrine neoplasia type 2A (MEN2A). Functional characterization of the p.Cys634Tyr variant and other missense variants at the same amino acid position (p.Cys634Arg, p.Cys634Trp) indicated increased auto-phosphorylation and activation of downstream targets, resulting in enhanced malignant transformation of cells (Cosci et al., 2011, Santoro et al., 1995). This variant is present with allele frequency of 0.0004% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic/ Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Cys634Tyr in RET is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 634 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: RET c.1901G>A (p.Cys634Tyr) results in a non-conservative amino acid change located in the extracellular domain of 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 247574 control chromosomes. c.1901G>A has been well reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2A (example Chiefari_1998, Frank-Raue_2006). These data indicate that the variant is strongly associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating a gain of function mechanism due to activation of the RET proto-oncogene (example Santoro_1995). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. The American Thyroid Association has placed this variant into the ATA-H category, formerly known as level C, for having a high risk of developing aggressive medullary thyroid carcinoma (MTC; see PMID: 25810047). This variant segregates with disease in multiple families. Computational tools predict that this variant is damaging.
Comment:
Published functional studies demonstrate a damaging effect: high transforming ability, constitutive kinase activation (Santoro 1995, Ito 1997); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(Cys380Tyr); This variant is associated with the following publications: (PMID: 12711285, 8797874, 9146685, 23723040, 19062722, 27558615, 25515555, 26254625, 29133048, 29656518, 23330657, 7835899, 21765987, 7824936, 8099202, 15858153, 8626834, 21054478, 16314641, 17895320, 24716929, 12000816, 7874109, 20080836, 26732158, 28099363, 26758973, 26572832, 26876062, 27539324, 23868299, 11987030, 30139385, 29197744, 7881414, 9230192, 28469506, 30113649, 21655256, 18063059, 12686527, 9950371, 7860065, 16099853, 11524247, 19240193, 7914213, 7491519, 12604374, 9820617, 9699127, 31062739, 30122763, 16158949, 20516206, 29625052, 31510104, 32989896, 8909322, 18096130, 9497883, 8984233, 35627249, 28152038, 30763276, 9706252, 25545346, 33340421, 33219105, 35418818, 14633923)
Comment:
The family RET mutation (C634Y) was detected in this blood specimen. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 634 of the RET protein (p.Cys634Tyr). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A and medullary thyroid cancer and pheochromocytoma (PMID: 2008030, 8099202, 12000816, 23723040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13909) with 22 submissions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RET function (PMID: 7824936). 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: 8099202, 12000816, 21765987). Therefore, this variant has been classified as Pathogenic.
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9230192, 21834681]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26732158, 17188172, 34439168, 20801952, 33827484, 25810047].
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 634 of the RET protein (p.Cys634Tyr). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A and medullary thyroid cancer and pheochromocytoma (PMID: 2008030, 8099202, 12000816, 23723040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13909). 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. Experimental studies have shown that this missense change affects RET function (PMID: 7824936). 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: 8099202, 12000816, 21765987). 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.C634Y pathogenic mutation (also known as c.1901G>A) is located in coding exon 11 of the RET gene. This alteration results from a G to A substitution at nucleotide position 1901. The cysteine at codon 634 is replaced by tyrosine, an amino acid with highly dissimilar properties. The p.C634Y mutation has been reported in several unrelated families diagnosed with MEN2A and/or familial medullary thyroid carcinoma (FMTC) (Mulligan et al. Nature. 1993;363:458-460; Marsh DJ et al. Genomics. 1994;23(2):477-479; Hedayati et al. J Thyroid Res. 2011;2011:264248; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122). Amino acid position 634 is a well described mutation hot spot associated with MEN2A/FMTC. Studies evaluating genotype-phenotype correlation suggest higher penetrance for pheochromocytoma in MEN2 patients with mutations at amino acid position 634 (Neumann HP et al. N. Engl. J. Med. 2002;346:1459-66, Quayle FJ et al. Surgery 2007;142:800-5; Yip L et al. Arch Surg 2003;138:409-16). Revised American Thyroid Association Guidelines categorize the p.C634Y alteration as high risk (ATA-H) and recommend surveillance and prophylactic surgery in early childhood (Wells SA et al. Thyroid 2015 Jun;25(6):567-610). Of note, this alteration has been referred to as p.C380Y (c.1832G>A) and p.C634Y (c.2096G>A) in the published literature. Based on the available evidence, p.C634Y is classified as a pathogenic mutation.
Comment:
The RET c.1901G>A variant is predicted to result in the amino acid substitution p.Cys634Tyr. This variant has been reported in multiple individuals with MEN2A, medullary thyroid cancer, and pheochromocytoma (Mulligan et al. 1993. PubMed ID: 8099202; Sanchez et al. 1999. PubMed ID: 9950371; Toledo et al. 2010. PubMed ID: 20080836). Functional studies have shown this variant and other amino acid changes at this position result in increased auto-phosphorylation and activation of downstream targets which enhances malignant transformation of cells (Santoro M et al. 1995. PubMed ID: 7824936; Cosci B et al. 2011. PubMed ID: 21810974). This variant is present in one individual in the gnomAD database. This variant is classified as pathogenic in ClinVar with multiple submitters in agreement (https://www.ncbi.nlm.nih.gov/clinvar/variation/13909/). We interpret this variant to be pathogenic.
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.1901G>A;p.Cys634Tyr variant (rs75996173) is reported in the literature in multiple individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (American Thyroid Association Guidelines Task Force 2009, Punales 2003, Wells 2015). This variant is found on a single chromosome in the Genome Aggregation Database (1/247574 alleles), indicating it is not a common polymorphism. The cysteine at codon 634 is highly conserved, and other amino acid substitutions at this codon (Arg, Gly, Phe, Ser, Trp) are considered causative for MEN2A (Wells 2015). Functional characterization of the p.Cys364Tyr variant and other missense variants at the same codon (p.Cys634Arg, p.Cys634Trp) indicates increased auto-phosphorylation and activation of downstream targets (Santoro 1995), resulting in enhanced malignant transformation of cells (Cosci 2011, Santoro 1995). Based on available information, the p.Cys634Tyr variant is considered to be pathogenic. References: American Thyroid Association Guidelines Task Force et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 Jun;19(6):565-612. Cosci B et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer. 2011 Sep 20;18(5):603-12. Punales MK et al. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003 Jun;88(6):2644-9. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995 Jan 20;267(5196):381-3. Wells S et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610.
Comment:
The RET c.1901G>A (p.Cys634Tyr) variant has been reported in the published literature in multiple individuals with MEN2A and/or FMTC (PMID: 7835899 (1994), 9950371 (1999), 12000816 (2002), 21765987 (2011), 25810047 (2015), 26732158 (2016), 28099363 (2017), 33167350 (2020)). A functional study found the variant has a damaging effect on RET function (PMID: 7824936 (2015)). The frequency of this variant in the general population, 0.000004 (1/247574 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Comment:
The observed missense c.1901G>A (p.Cys634Tyr) variant in RET gene has been reported in multiple individuals affected with RET-related disorders (Chiefari et al., 1998; Sánchez et al., 1999; Jackson et al., 2005; Valente et al., 2013; Valdés et al., 2015). It has also been observed to segregate with disease in related individuals (Valente et al., 2013). Amino acid position 634 is a well described mutation hot spot associated with Multiple endocrine neoplasia type 2A (MEN2A). Functional characterization of the p.Cys634Tyr variant and other missense variants at the same amino acid position (p.Cys634Arg, p.Cys634Trp) indicated increased auto-phosphorylation and activation of downstream targets, resulting in enhanced malignant transformation of cells (Cosci et al., 2011, Santoro et al., 1995). This variant is present with allele frequency of 0.0004% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic/ Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Cys634Tyr in RET is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 634 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: RET c.1901G>A (p.Cys634Tyr) results in a non-conservative amino acid change located in the extracellular domain of 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 247574 control chromosomes. c.1901G>A has been well reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2A (example Chiefari_1998, Frank-Raue_2006). These data indicate that the variant is strongly associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating a gain of function mechanism due to activation of the RET proto-oncogene (example Santoro_1995). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. The American Thyroid Association has placed this variant into the ATA-H category, formerly known as level C, for having a high risk of developing aggressive medullary thyroid carcinoma (MTC; see PMID: 25810047). This variant segregates with disease in multiple families. Computational tools predict that this variant is damaging.
Comment:
Published functional studies demonstrate a damaging effect: high transforming ability, constitutive kinase activation (Santoro 1995, Ito 1997); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(Cys380Tyr); This variant is associated with the following publications: (PMID: 12711285, 8797874, 9146685, 23723040, 19062722, 27558615, 25515555, 26254625, 29133048, 29656518, 23330657, 7835899, 21765987, 7824936, 8099202, 15858153, 8626834, 21054478, 16314641, 17895320, 24716929, 12000816, 7874109, 20080836, 26732158, 28099363, 26758973, 26572832, 26876062, 27539324, 23868299, 11987030, 30139385, 29197744, 7881414, 9230192, 28469506, 30113649, 21655256, 18063059, 12686527, 9950371, 7860065, 16099853, 11524247, 19240193, 7914213, 7491519, 12604374, 9820617, 9699127, 31062739, 30122763, 16158949, 20516206, 29625052, 31510104, 32989896, 8909322, 18096130, 9497883, 8984233, 35627249, 28152038, 30763276, 9706252, 25545346, 33340421, 33219105, 35418818, 14633923)
Comment:
The family RET mutation (C634Y) was detected in this blood specimen. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 634 of the RET protein (p.Cys634Tyr). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A and medullary thyroid cancer and pheochromocytoma (PMID: 2008030, 8099202, 12000816, 23723040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13909) with 22 submissions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RET function (PMID: 7824936). 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: 8099202, 12000816, 21765987). Therefore, this variant has been classified as Pathogenic.
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9230192, 21834681]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26732158, 17188172, 34439168, 20801952, 33827484, 25810047].
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 634 of the RET protein (p.Cys634Tyr). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A and medullary thyroid cancer and pheochromocytoma (PMID: 2008030, 8099202, 12000816, 23723040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13909). 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. Experimental studies have shown that this missense change affects RET function (PMID: 7824936). 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: 8099202, 12000816, 21765987). 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.C634Y pathogenic mutation (also known as c.1901G>A) is located in coding exon 11 of the RET gene. This alteration results from a G to A substitution at nucleotide position 1901. The cysteine at codon 634 is replaced by tyrosine, an amino acid with highly dissimilar properties. The p.C634Y mutation has been reported in several unrelated families diagnosed with MEN2A and/or familial medullary thyroid carcinoma (FMTC) (Mulligan et al. Nature. 1993;363:458-460; Marsh DJ et al. Genomics. 1994;23(2):477-479; Hedayati et al. J Thyroid Res. 2011;2011:264248; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122). Amino acid position 634 is a well described mutation hot spot associated with MEN2A/FMTC. Studies evaluating genotype-phenotype correlation suggest higher penetrance for pheochromocytoma in MEN2 patients with mutations at amino acid position 634 (Neumann HP et al. N. Engl. J. Med. 2002;346:1459-66, Quayle FJ et al. Surgery 2007;142:800-5; Yip L et al. Arch Surg 2003;138:409-16). Revised American Thyroid Association Guidelines categorize the p.C634Y alteration as high risk (ATA-H) and recommend surveillance and prophylactic surgery in early childhood (Wells SA et al. Thyroid 2015 Jun;25(6):567-610). Of note, this alteration has been referred to as p.C380Y (c.1832G>A) and p.C634Y (c.2096G>A) in the published literature. Based on the available evidence, p.C634Y is classified as a pathogenic mutation.
Comment:
The RET c.1901G>A variant is predicted to result in the amino acid substitution p.Cys634Tyr. This variant has been reported in multiple individuals with MEN2A, medullary thyroid cancer, and pheochromocytoma (Mulligan et al. 1993. PubMed ID: 8099202; Sanchez et al. 1999. PubMed ID: 9950371; Toledo et al. 2010. PubMed ID: 20080836). Functional studies have shown this variant and other amino acid changes at this position result in increased auto-phosphorylation and activation of downstream targets which enhances malignant transformation of cells (Santoro M et al. 1995. PubMed ID: 7824936; Cosci B et al. 2011. PubMed ID: 21810974). This variant is present in one individual in the gnomAD database. This variant is classified as pathogenic in ClinVar with multiple submitters in agreement (https://www.ncbi.nlm.nih.gov/clinvar/variation/13909/). We interpret this variant to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| RET c.1901G>A and Novel SLC12A3 Mutations in Familial Pheochromocytomas. | Zhao L | Genes | 2022 | PMID: 35627249 |
| Characteristics of germline mutations in Korean patients with pheochromocytoma/paraganglioma. | Kim JH | Journal of medical genetics | 2022 | PMID: 33219105 |
| Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma. | Yonamine M | Cancers | 2021 | PMID: 34439168 |
| Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China. | Qi XP | BMC cancer | 2021 | PMID: 33827484 |
| Results and Clinical Interpretation of Germline RET Analysis in a Series of Patients with Medullary Thyroid Carcinoma: The Challenge of the Variants of Uncertain Significance. | Innella G | Cancers | 2020 | PMID: 33167350 |
| Genotype-specific progression of hereditary medullary thyroid cancer. | Machens A | Human mutation | 2018 | PMID: 29656518 |
| Preimplantation Genetic Diagnosis of Multiple Endocrine Neoplasia Type 2A Using Informative Markers Identified by Targeted Sequencing. | Chen S | Thyroid : official journal of the American Thyroid Association | 2018 | PMID: 29378479 |
| Transcriptional landscape of a RET(C634Y)-mutated iPSC and its CRISPR-corrected isogenic control reveals the putative role of EGR1 transcriptional program in the development of multiple endocrine neoplasia type 2A-associated cancers. | Hadoux J | Stem cell research | 2018 | PMID: 29197744 |
| Structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of inhibitors of RET and its drug resistance mutants. | Yang J | European journal of medicinal chemistry | 2018 | PMID: 29133048 |
| Genotype-Phenotype Correlation in Patients With Germline Mutations of VHL, RET, SDHB, and SDHD Genes: Thai Experience. | Sriphrapradang C | Clinical medicine insights. Endocrinology and diabetes | 2017 | PMID: 28469506 |
| Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. | LaDuca H | PloS one | 2017 | PMID: 28152038 |
| Different RET gene mutation-induced multiple endocrine neoplasia type 2A in 3 Chinese families. | Liu Q | Medicine | 2017 | PMID: 28099363 |
| Germline mutations and genotype-phenotype correlation in Asian Indian patients with pheochromocytoma and paraganglioma. | Pandit R | European journal of endocrinology | 2016 | PMID: 27539324 |
| Multiple endocrine neoplasia type 2 kindred with novel tandem RET mutations: Case report with an applied in silico mutational tolerance analysis. | Joshi RR | Head & neck | 2016 | PMID: 26876062 |
| Presence of the RET Cys634Tyr mutation and Gly691Ser functional polymorphism in Iranian families with multiple endocrine neoplasia type 2A. | Aghdam MN | Hormones (Athens, Greece) | 2016 | PMID: 26732158 |
| 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 |
| RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation. | Valdés N | European journal of endocrinology | 2015 | PMID: 25515555 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| 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 |
| Pheochromocytoma in an 8-year-old patient with multiple endocrine neoplasia type 2A: implications for screening. | Rowland KJ | Journal of surgical oncology | 2013 | PMID: 23868299 |
| Comprehensive analysis of RET gene should be performed in patients with multiple endocrine neoplasia type 2 (MEN 2) syndrome and no apparent genotype-phenotype correlation: an appraisal of p.Y791F and p.C634Y RET mutations in five unrelated Brazilian families. | Valente FO | Journal of endocrinological investigation | 2013 | PMID: 23723040 |
| An unusual genotype-phenotype correlation in MEN 2 patients: should screening for RET double germline mutations be performed to avoid misleading diagnosis and treatment? | Cerutti JM | Clinical endocrinology | 2013 | PMID: 23330657 |
| The RET p.G533C mutation confers predisposition to multiple endocrine neoplasia type 2A in a Brazilian kindred and is able to induce a malignant phenotype in vitro and in vivo. | Oliveira MN | Thyroid : official journal of the American Thyroid Association | 2011 | PMID: 21834681 |
| 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 |
| RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family. | Qi XP | PloS one | 2011 | PMID: 21655256 |
| The RET polymorphic allele S836S is associated with early metastatic disease in patients with hereditary or sporadic medullary thyroid carcinoma. | Siqueira DR | Endocrine-related cancer | 2010 | PMID: 20801952 |
| High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene. | Toledo RA | The Journal of clinical endocrinology and metabolism | 2010 | PMID: 20080836 |
| 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 |
| [Tumor dormancy of hereditary medullary thyroid carcinoma and RET gene mutations]. | Yü Y | Zhonghua zhong liu za zhi [Chinese journal of oncology] | 2008 | PMID: 19062722 |
| [Retroperitoneal laparoscopic adrenalectomy in a pregnant woman presenting MEN2a with a pheochromocytoma: case report and review of the literature]. | Frayssinet C | Annales d'endocrinologie | 2008 | PMID: 18096130 |
| Pheochromocytoma penetrance varies by RET mutation in MEN 2A. | Quayle FJ | Surgery | 2007 | PMID: 18063059 |
| Mutation analysis of the RET proto-oncogene and early thyroidectomy: results of a Portuguese cancer centre. | Bugalho MJ | Surgery | 2007 | PMID: 17188172 |
| 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 |
| Multiple endocrine neoplasia type 2A in a kindred with C634Y mutation. | Jackson MB | Pediatrics | 2005 | PMID: 16099853 |
| Penetrance of inherited medullary thyroid carcinoma and genotype-phenotype correlation in a large multiple endocrine neoplasia type 2A family with C634Y RET mutation. | González-Yebra B | Endocrine pathology | 2003 | PMID: 12746565 |
| Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. | Yip L | Archives of surgery (Chicago, Ill. : 1960) | 2003 | PMID: 12686527 |
| Germ-line mutations in nonsyndromic pheochromocytoma. | Neumann HP | The New England journal of medicine | 2002 | PMID: 12000816 |
| Molecular and biochemical screening for the diagnosis and management of medullary thyroid carcinoma in multiple endocrine neoplasia type 2A. | Vieira AE | Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | 2002 | PMID: 11987030 |
| 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 |
| Analysis of RET proto-oncogene abnormalities in patients with MEN 2A, MEN 2B, familial or sporadic medullary thyroid carcinoma. | Chiefari E | Journal of endocrinological investigation | 1998 | PMID: 9699127 |
| 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 |
| Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease. | Eng C | Human mutation | 1997 | PMID: 9067749 |
| RET activation by germline MEN2A and MEN2B mutations. | Borrello MG | Oncogene | 1995 | PMID: 8570194 |
| Germline mutations of the RET proto-oncogene in eight Japanese patients with multiple endocrine neoplasia type 2A (MEN2A). | Takiguchi-Shirahama S | Human genetics | 1995 | PMID: 7860065 |
| 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 |
| Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests. | Xue F | Human molecular genetics | 1994 | PMID: 7915165 |
| Identification of the Cys634-->Tyr mutation of the RET proto-oncogene in a pedigree with multiple endocrine neoplasia type 2A and localized cutaneous lichen amyloidosis. | Ceccherini I | Journal of endocrinological investigation | 1994 | PMID: 7914213 |
| Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. | Mulligan LM | Nature genetics | 1994 | PMID: 7907913 |
| Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. | Mulligan LM | Human molecular genetics | 1994 | PMID: 7881414 |
| 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 |
| Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. | Mulligan LM | Nature | 1993 | PMID: 8099202 |
| Beyond generic occurrence screening. | O'Leary DS | JAMA | 1991 | PMID: 2008030 |
| Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. | Takahashi M | Oncogene | 1988 | PMID: 3078962 |
| http://docm.genome.wustl.edu/variants/ENST00000340058:c.1901G>A | - | - | - | - |
| http://docm.genome.wustl.edu/variants/ENST00000355710:c.1901G>A | - | - | - | - |
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Text-mined citations for rs75996173 ...
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Record last updated Nov 25, 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.