The RET c.2753T>C, p.Met918Thr variant has been reported in multiple patients diagnosed with multiple endocrine neoplasia type 2b (Carlson 1994, Jindrichova 2004), co-segregated with affected family members, or occurred as a de novo alteration (Carlson 1994) and has been reported to confer high risk (Wells 2015). Functional characterization of the variant protein indicates an increase in basal auto-phosphorylation that is further enhanced upon growth factor stimulation, with altered target specificity compared to wildtype protein (Bongarzone 1998, Santoro 1995). The variant is listed in the dbSNP variant database (rs74799832), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Exome Aggregation Consortium). The methionine at residue 918 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic. References: Bongarzone I et al. Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation. Oncogene. 1998; 16(18):2295-301. Carlson K et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A. 1994; 91(4):1579-83. Jindrichova S et al. Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J Endocrinol. 2004; 183(2):257-65. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995; 267(5196):381-3. Wells SA Jr 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.2753T>C (p.Met918Thr)
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.
(42)
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/Likely pathogenic
42
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.2753T>C (p.Met918Thr)
Variation ID: 13919 Accession: VCV000013919.56
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q11.21 10: 43121968 (GRCh38) [ NCBI UCSC ] 10: 43617416 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 13, 2017 Oct 8, 2024 Mar 29, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.2753T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Met918Thr missense NM_000323.2:c.2753T>C NP_000314.1:p.Met918Thr missense NM_001355216.2:c.1991T>C NP_001342145.1:p.Met664Thr missense NM_001406743.1:c.2753T>C NP_001393672.1:p.Met918Thr missense NM_001406744.1:c.2753T>C NP_001393673.1:p.Met918Thr missense NM_001406759.1:c.2753T>C NP_001393688.1:p.Met918Thr missense NM_001406760.1:c.2753T>C NP_001393689.1:p.Met918Thr missense NM_001406761.1:c.2624T>C NP_001393690.1:p.Met875Thr missense NM_001406762.1:c.2624T>C NP_001393691.1:p.Met875Thr missense NM_001406763.1:c.2618T>C NP_001393692.1:p.Met873Thr missense NM_001406764.1:c.2624T>C NP_001393693.1:p.Met875Thr missense NM_001406765.1:c.2618T>C NP_001393694.1:p.Met873Thr missense NM_001406766.1:c.2465T>C NP_001393695.1:p.Met822Thr missense NM_001406767.1:c.2465T>C NP_001393696.1:p.Met822Thr missense NM_001406768.1:c.2489T>C NP_001393697.1:p.Met830Thr missense NM_001406769.1:c.2357T>C NP_001393698.1:p.Met786Thr missense NM_001406770.1:c.2465T>C NP_001393699.1:p.Met822Thr missense NM_001406771.1:c.2315T>C NP_001393700.1:p.Met772Thr missense NM_001406772.1:c.2357T>C NP_001393701.1:p.Met786Thr missense NM_001406773.1:c.2315T>C NP_001393702.1:p.Met772Thr missense NM_001406774.1:c.2228T>C NP_001393703.1:p.Met743Thr missense NM_001406775.1:c.2027T>C NP_001393704.1:p.Met676Thr missense NM_001406776.1:c.2027T>C NP_001393705.1:p.Met676Thr missense NM_001406777.1:c.2027T>C NP_001393706.1:p.Met676Thr missense NM_001406778.1:c.2027T>C NP_001393707.1:p.Met676Thr missense NM_001406779.1:c.1856T>C NP_001393708.1:p.Met619Thr missense NM_001406780.1:c.1856T>C NP_001393709.1:p.Met619Thr missense NM_001406781.1:c.1856T>C NP_001393710.1:p.Met619Thr missense NM_001406782.1:c.1856T>C NP_001393711.1:p.Met619Thr missense NM_001406783.1:c.1727T>C NP_001393712.1:p.Met576Thr missense NM_001406784.1:c.1763T>C NP_001393713.1:p.Met588Thr missense NM_001406785.1:c.1736T>C NP_001393714.1:p.Met579Thr missense NM_001406786.1:c.1727T>C NP_001393715.1:p.Met576Thr missense NM_001406787.1:c.1721T>C NP_001393716.1:p.Met574Thr missense NM_001406788.1:c.1568T>C NP_001393717.1:p.Met523Thr missense NM_001406789.1:c.1568T>C NP_001393718.1:p.Met523Thr missense NM_001406790.1:c.1568T>C NP_001393719.1:p.Met523Thr missense NM_001406791.1:c.1448T>C NP_001393720.1:p.Met483Thr missense NM_001406792.1:c.1304T>C NP_001393721.1:p.Met435Thr missense NM_001406793.1:c.1304T>C NP_001393722.1:p.Met435Thr missense NM_001406794.1:c.1304T>C NP_001393723.1:p.Met435Thr missense NM_020629.2:c.2753T>C NP_065680.1:p.Met918Thr missense NM_020630.7:c.2753T>C NP_065681.1:p.Met918Thr missense NC_000010.11:g.43121968T>C NC_000010.10:g.43617416T>C NG_007489.1:g.49900T>C LRG_518:g.49900T>C LRG_518t1:c.2753T>C LRG_518p1:p.Met918Thr LRG_518t2:c.2753T>C LRG_518p2:p.Met918Thr P07949:p.Met918Thr - Protein change
- M918T, M664T, M579T, M676T, M772T, M786T, M875T, M830T, M873T, M483T, M574T, M588T, M743T, M822T, M435T, M576T, M619T, M523T
- Other names
-
p.M918T:ATG>ACG
- Canonical SPDI
- NC_000010.11:43121967:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 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 (1) |
no assertion criteria provided
|
May 7, 1998 | RCV000014942.31 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 7, 1998 | RCV000014943.14 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
May 21, 2023 | RCV000014941.45 | |
| Pathogenic (12) |
criteria provided, multiple submitters, no conflicts
|
Nov 10, 2023 | RCV000082054.41 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 15, 2020 | RCV000175096.16 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 8, 2014 | RCV000415312.10 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 13, 2016 | RCV000425499.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Oct 2, 2014 | RCV000428538.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 22, 2023 | RCV000161926.22 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Aug 2, 2017 | RCV000417859.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 13, 2016 | RCV000444529.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 16, 2019 | RCV000999916.15 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 23, 2022 | RCV001292662.10 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 29, 2024 | RCV001542764.12 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 11, 2022 | RCV002255998.11 | |
|
RET-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Feb 21, 2024 | RCV004532351.2 |
| 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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 08, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Constipation
Gingival overgrowth Hypertelorism Hypothyroidism Joint hypermobility Short stature Tetralogy of Fallot Thick vermilion border
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492883.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
|
|
|
Pathogenic
(Aug 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Medullary thyroid carcinoma
Affected status: yes
Allele origin:
germline
|
3DMed Clinical Laboratory Inc
Accession: SCV000804060.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Apr 16, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605028.3
First in ClinVar: Sep 30, 2017 Last updated: Feb 10, 2020 |
Comment:
The RET c.2753T>C, p.Met918Thr variant has been reported in multiple patients diagnosed with multiple endocrine neoplasia type 2b (Carlson 1994, Jindrichova 2004), co-segregated with affected … (more)
The RET c.2753T>C, p.Met918Thr variant has been reported in multiple patients diagnosed with multiple endocrine neoplasia type 2b (Carlson 1994, Jindrichova 2004), co-segregated with affected family members, or occurred as a de novo alteration (Carlson 1994) and has been reported to confer high risk (Wells 2015). Functional characterization of the variant protein indicates an increase in basal auto-phosphorylation that is further enhanced upon growth factor stimulation, with altered target specificity compared to wildtype protein (Bongarzone 1998, Santoro 1995). The variant is listed in the dbSNP variant database (rs74799832), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Exome Aggregation Consortium). The methionine at residue 918 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic. References: Bongarzone I et al. Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation. Oncogene. 1998; 16(18):2295-301. Carlson K et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A. 1994; 91(4):1579-83. Jindrichova S et al. Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J Endocrinol. 2004; 183(2):257-65. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995; 267(5196):381-3. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015; 25(6):567-610. (less)
|
|
|
Pathogenic
(Dec 17, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial medullary thyroid carcinoma
Affected status: yes
Allele origin:
de novo
|
Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001481264.2 First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 7906417, 17540634, 8570194, … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 7906417, 17540634, 8570194, 19169500, 22359510, 21810974, 23660872, 24336963, 21765987] (less)
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hirschsprung disease, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760250.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
|
|
|
Pathogenic
(Aug 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2B
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579378.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS2, PS3_MOD, PS4_MOD, PM2_SUP, PP3
|
Number of individuals with the variant: 2
Sex: male
|
|
|
Pathogenic
(Apr 20, 2023)
|
criteria provided, single submitter
Method: research
|
Multiple endocrine neoplasia type 2B
Affected status: yes
Allele origin:
de novo
|
Duke University Health System Sequencing Clinic, Duke University Health System
Accession: SCV003918924.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
|
|
|
Pathogenic
(Jan 13, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000510661.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
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: SCV000782260.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
|
|
|
Pathogenic
(Nov 29, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000226525.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 8
Sex: mixed
|
|
|
Pathogenic
(Jul 24, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000842759.2
First in ClinVar: Oct 19, 2018 Last updated: Jan 18, 2020 |
Comment:
Widely published variant reported to account for 95% of MEN2B cases. The best available variant frequency is uninformative because there are too few occurrences in … (more)
Widely published variant reported to account for 95% of MEN2B cases. The best available variant frequency is uninformative because there are too few occurrences in population data. Found in multiple symptomatic patients. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Multiple de novo cases reported in the literature. In familial cases, variant segregates with disease. (less)
|
|
|
Pathogenic
(Jul 03, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450291.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 8
|
|
|
Pathogenic
(Dec 15, 2020)
|
criteria provided, single submitter
Method: research
|
Multiple endocrine neoplasia type 2A
Affected status: no
Allele origin:
germline
|
Department of Pediatrics, Memorial Sloan Kettering Cancer Center
Accession: SCV001478177.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
|
|
|
Pathogenic
(Aug 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2B
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001821474.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Variant summary: RET c.2753T>C (p.Met918Thr) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five … (more)
Variant summary: RET c.2753T>C (p.Met918Thr) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) 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 251618 control chromosomes. c.2753T>C has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2B (example, Carlson_1994, Elisei_2007, Hofstra_1994). These data indicate that the variant is very likely to be associated with disease. Multiple publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significant increase in tyrosine kinase activity resulting in a transforming activation of the RET proto-oncogene (example, Borrello_1995). Multiple 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 01, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002529992.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The RET c.2753T>C (p.M918T) variant has been reported in heterozygosity in numerous individuals with MEN2B (PMID: 7906417, 8918855, 20516206, 17963006, 31510104, 30660595). The variant has … (more)
The RET c.2753T>C (p.M918T) variant has been reported in heterozygosity in numerous individuals with MEN2B (PMID: 7906417, 8918855, 20516206, 17963006, 31510104, 30660595). The variant has been observed to segregate with disease within families, as well as many de novo cases (PMID: 7906417). This variant causes approximately 95% of all MEN2B cases (PMID: 8918855, 17963006). Functional studies have shown that this variant alters the activation of RET kinase causing increased transforming capacity (PMID: 9242375, 16715139). This variant was observed in 1/113754 chromosomes in the Non-Finnish European population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 13919). In silico tools suggest the impact of the variant on protein function is deleterious. Based on the current evidence available, this variant is interpreted as pathogenic. (less)
|
|
|
|
Pathogenic
(Oct 21, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000677723.2
First in ClinVar: Mar 08, 2017 Last updated: Dec 24, 2022 |
Comment:
M918T is associated only with MEN2B phenotype.
|
|
|
Pathogenic
(Mar 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000234940.13
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Most common RET variant reported in association with MEN2B (Carlson 1994, Eng 1996, Brauckhoff 2004, Wray 2008); Published functional studies demonstrate a damaging effect: increased … (more)
Most common RET variant reported in association with MEN2B (Carlson 1994, Eng 1996, Brauckhoff 2004, Wray 2008); Published functional studies demonstrate a damaging effect: increased transforming ability, cellular proliferation, and tyrosine phosphorylation (Pasini 1997, Cosci 2011); 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); This variant is associated with the following publications: (PMID: 10679286, 8570194, 30763276, 20516206, 15517484, 22359510, 10369718, 26843961, 23225389, 30660595, 18252215, 19826964, 11720239, 21765987, 9242375, 21810974, 7906417, 24336963, 23660265, 26294908, 23660872, 8918855, 7824936, 27807060, 27539324, 17963006, 29182461, 17540634, 19169500, 29396759, 16481266, 9541448, 18631354, 17576593, 17848262, 16808642, 26084817, 31510104, 29625052, 34308366, 33268590, 32561571, 8909322, 9706252, 33191720, 30624503, 32546069, 14633923) (less)
|
|
|
Pathogenic
(Apr 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2B
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004018499.1
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: 16715139, 9242375, 21810974]. This variant has been reported in multiple individuals … (more)
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16715139, 9242375, 21810974]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7906417, 34629742, 29656518, 34881033, 25810047]. (less)
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|
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Pathogenic
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004027576.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
|
|
|
Pathogenic
(May 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2B
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)
Accession: SCV003930405.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Number of individuals with the variant: 2
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|
|
Pathogenic
(Dec 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial medullary thyroid carcinoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175521.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
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Pathogenic
(Jun 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002522521.2
First in ClinVar: Jun 05, 2022 Last updated: Jan 26, 2024 |
Comment:
PP4, PP5, PM1, PM2, PS3, PS4_moderate
Number of individuals with the variant: 12
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|
|
Pathogenic
(Oct 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020786.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Dec 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000211909.13
First in ClinVar: Feb 28, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 918 of the RET protein (p.Met918Thr). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 918 of the RET protein (p.Met918Thr). This variant is present in population databases (rs74799832, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant multiple endocrine neoplasia type 2 (PMID: 7906417, 8918855, 16715139, 20516206, 27539324). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13919). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RET function (PMID: 8570194, 9242375, 16715139, 21810974). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 29, 2024)
|
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: SCV004807988.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Mar 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002750282.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.M918T pathogenic mutation (also known as c.2753T>C), located in coding exon 16 of the RET gene, results from a T to C substitution at … (more)
The p.M918T pathogenic mutation (also known as c.2753T>C), located in coding exon 16 of the RET gene, results from a T to C substitution at nucleotide position 2753. The methionine at codon 918 is replaced by threonine, an amino acid with similar properties. This mutation is located in the catalytic core of the tyrosine kinase domain, within a highly conserved region of the RET protein. This mutation was first described in 58 individuals with a clinical diagnosis of multiple endocrine neoplasia type 2B (MEN2B) (Carlson KM et al. Proc. Natl. Acad. Sci. U.S.A. 1994;91(4):1579-83), and has since been well described in numerous other affected individuals (Choi S et al. PLoS Genet. 2012;8(2):e1002420; Hedayati M et al. J Thyroid Res. 2011;2011:264248; Smith V et al. Gut. 1999 Jul;45(1):143-6). In another study, this mutation was described in 95% (75/79) of MEN2B families (Eng C et al. JAMA 1996;276(19):1575-9). Per the revised American Thyroid Associated guidelines, individuals with alterations at codon 918 in the RET gene are at highest risk for MTC with recommended screenings and/or surgical interventions beginning in early childhood (Wells SA et al. Thyroid 2015 Jun; 25(6):567-610). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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|
|
Pathogenic
(Nov 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198059.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(May 07, 1998)
|
no assertion criteria provided
Method: literature only
|
PHEOCHROMOCYTOMA, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000035199.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2017 |
Comment on evidence:
In all 9 unrelated MEN2B patients studied, Hofstra et al. (1994) found a mutation in codon 918 of the RET gene, causing the substitution of … (more)
In all 9 unrelated MEN2B patients studied, Hofstra et al. (1994) found a mutation in codon 918 of the RET gene, causing the substitution of a threonine for a methionine in the tyrosine kinase domain of the protein. They found the same mutation in 6 of 18 sporadic medullary thyroid carcinomas (155240). This conclusively demonstrates that MEN2A and MEN2B are related as allelic disorders; there is thus no justification for calling MEN2B MEN3. This identical point mutation in the catalytic core of the tyrosine kinase domain of RET was also found in association with both inherited and de novo MEN2B by Carlson et al. (1994) and Eng et al. (1994). The ATG-to-ACG mutation results in the substitution of threonine for methionine at codon 918 in the codon designation of Takahashi et al. (1988, 1989). Carlson et al. (1994) proposed that this amino acid replacement affects substrate interactions and results in oncogenic action by the RET protein. It is noteworthy that most mutations identified in cases of MEN2A and familial medullary thyroid carcinoma have been contained within the extracellular ligand-binding domain of the RET protooncogene and have resulted in nonconservative substitutions for 4 different cysteines. MEN2B has shown mainly noncysteine substitutions. The existence of polymorphic markers tightly linked to MEN2B and the fact that the M918T mutation accounts for almost all cases of MEN2B enabled Carlson et al. (1994) to determine unequivocally whether mutations occurred on the maternal or paternal chromosome. Strikingly, all 25 of the mutations they analyzed occurred in the paternal allele. Therefore, MEN2B can be added to the list of neoplastic diseases, which already includes Wilms tumor, bilateral retinoblastoma, osteosarcoma, embryonal rhabdomyosarcoma, and neurofibromatosis type I, for which the relevant genetic alteration occurs either predominantly or exclusively on the paternally derived chromosome. Carlson et al. (1994) also observed a paternal age effect. Santoro et al. (1995) demonstrated that this RET allele is a transforming gene in NIH 3T3 cells as a consequence of constitutive activation of the RET kinase. The mutation alters RET catalytic properties both quantitatively and qualitatively. Eng et al. (1995) analyzed 71 sporadic medullary thyroid carcinomas (68 primary tumors and 3 cell lines) for mutations in RET exons 10, 11, and 16. They found that 23% of sporadic MTC had RET codon 918 mutations (located in exon 16), while only 3% had exon 10 mutations and none had mutations in exon 11. They found no exon 16 mutations in MTC from 14 MEN2A cases. Thus, exon 10 and 11 mutations, commonly found in familial MTC and MEN2A, rarely occur in sporadic MTC; somatic mutation of RET codon 918 appears to play a role in the tumorigenesis of a significant minority of sporadic MTC but not in MEN2A tumors. In addition to their biologic interest, these findings may have clinical application in determining whether a case presenting with isolated MTC is truly sporadic or is part of an inherited cancer syndrome. The codon 918 mutation altered methionine (ATG) to threonine (ACG). In all instances in which germline DNA was available for analysis, it was found to be wildtype. This mutation was previously designated MET664THR. Eng et al. (1995) identified the M918T substitution in pheochromocytoma (171300) tumor tissue from 2 unrelated patients. The mutation was not identified in the germline of these patients. In MEN2A, mutations affecting cysteine residues in the extracellular domain of the receptor tyrosine kinase cause constitutive activation of the tyrosine kinase by the formation of disulfide-bonded homodimers. In MEN2B, only the met918-to-thr mutation in the tyrosine kinase domain has been identified. This mutation does not lead to dimer formation, but has been shown both biologically and biochemically to cause ligand-independent activation of the RET protein, but to a lesser extent than MEN2A mutations. Bongarzone et al. (1998) showed that the activity of the MEN2B RET mutation could be increased by stable dimerization of the receptor. Dimerization was achieved experimentally by constructing a double mutant receptor with a MEN2A mutation (cys634 to arg; 164761.0011) in addition to the MEN2B mutation, and by chronic exposure of the cells expressing the met918-to-thr mutation of RET to the RET ligand glial cell line-derived neurotrophic factor (GDNF; 600837). In both cases, full activation of the RET-MEN2B mutant protein, measured by in vitro transfection assays and biochemical parameters, was seen. These results indicated that the MEN2B phenotype could be influenced by the tissue distribution or concentration of RET ligand(s). (less)
|
|
|
Pathogenic
(May 07, 1998)
|
no assertion criteria provided
Method: literature only
|
MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000035197.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2017 |
Comment on evidence:
In all 9 unrelated MEN2B patients studied, Hofstra et al. (1994) found a mutation in codon 918 of the RET gene, causing the substitution of … (more)
In all 9 unrelated MEN2B patients studied, Hofstra et al. (1994) found a mutation in codon 918 of the RET gene, causing the substitution of a threonine for a methionine in the tyrosine kinase domain of the protein. They found the same mutation in 6 of 18 sporadic medullary thyroid carcinomas (155240). This conclusively demonstrates that MEN2A and MEN2B are related as allelic disorders; there is thus no justification for calling MEN2B MEN3. This identical point mutation in the catalytic core of the tyrosine kinase domain of RET was also found in association with both inherited and de novo MEN2B by Carlson et al. (1994) and Eng et al. (1994). The ATG-to-ACG mutation results in the substitution of threonine for methionine at codon 918 in the codon designation of Takahashi et al. (1988, 1989). Carlson et al. (1994) proposed that this amino acid replacement affects substrate interactions and results in oncogenic action by the RET protein. It is noteworthy that most mutations identified in cases of MEN2A and familial medullary thyroid carcinoma have been contained within the extracellular ligand-binding domain of the RET protooncogene and have resulted in nonconservative substitutions for 4 different cysteines. MEN2B has shown mainly noncysteine substitutions. The existence of polymorphic markers tightly linked to MEN2B and the fact that the M918T mutation accounts for almost all cases of MEN2B enabled Carlson et al. (1994) to determine unequivocally whether mutations occurred on the maternal or paternal chromosome. Strikingly, all 25 of the mutations they analyzed occurred in the paternal allele. Therefore, MEN2B can be added to the list of neoplastic diseases, which already includes Wilms tumor, bilateral retinoblastoma, osteosarcoma, embryonal rhabdomyosarcoma, and neurofibromatosis type I, for which the relevant genetic alteration occurs either predominantly or exclusively on the paternally derived chromosome. Carlson et al. (1994) also observed a paternal age effect. Santoro et al. (1995) demonstrated that this RET allele is a transforming gene in NIH 3T3 cells as a consequence of constitutive activation of the RET kinase. The mutation alters RET catalytic properties both quantitatively and qualitatively. Eng et al. (1995) analyzed 71 sporadic medullary thyroid carcinomas (68 primary tumors and 3 cell lines) for mutations in RET exons 10, 11, and 16. They found that 23% of sporadic MTC had RET codon 918 mutations (located in exon 16), while only 3% had exon 10 mutations and none had mutations in exon 11. They found no exon 16 mutations in MTC from 14 MEN2A cases. Thus, exon 10 and 11 mutations, commonly found in familial MTC and MEN2A, rarely occur in sporadic MTC; somatic mutation of RET codon 918 appears to play a role in the tumorigenesis of a significant minority of sporadic MTC but not in MEN2A tumors. In addition to their biologic interest, these findings may have clinical application in determining whether a case presenting with isolated MTC is truly sporadic or is part of an inherited cancer syndrome. The codon 918 mutation altered methionine (ATG) to threonine (ACG). In all instances in which germline DNA was available for analysis, it was found to be wildtype. This mutation was previously designated MET664THR. Eng et al. (1995) identified the M918T substitution in pheochromocytoma (171300) tumor tissue from 2 unrelated patients. The mutation was not identified in the germline of these patients. In MEN2A, mutations affecting cysteine residues in the extracellular domain of the receptor tyrosine kinase cause constitutive activation of the tyrosine kinase by the formation of disulfide-bonded homodimers. In MEN2B, only the met918-to-thr mutation in the tyrosine kinase domain has been identified. This mutation does not lead to dimer formation, but has been shown both biologically and biochemically to cause ligand-independent activation of the RET protein, but to a lesser extent than MEN2A mutations. Bongarzone et al. (1998) showed that the activity of the MEN2B RET mutation could be increased by stable dimerization of the receptor. Dimerization was achieved experimentally by constructing a double mutant receptor with a MEN2A mutation (cys634 to arg; 164761.0011) in addition to the MEN2B mutation, and by chronic exposure of the cells expressing the met918-to-thr mutation of RET to the RET ligand glial cell line-derived neurotrophic factor (GDNF; 600837). In both cases, full activation of the RET-MEN2B mutant protein, measured by in vitro transfection assays and biochemical parameters, was seen. These results indicated that the MEN2B phenotype could be influenced by the tissue distribution or concentration of RET ligand(s). (less)
|
|
|
Pathogenic
(May 07, 1998)
|
no assertion criteria provided
Method: literature only
|
THYROID CARCINOMA, SPORADIC MEDULLARY
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000035198.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2017 |
Comment on evidence:
In all 9 unrelated MEN2B patients studied, Hofstra et al. (1994) found a mutation in codon 918 of the RET gene, causing the substitution of … (more)
In all 9 unrelated MEN2B patients studied, Hofstra et al. (1994) found a mutation in codon 918 of the RET gene, causing the substitution of a threonine for a methionine in the tyrosine kinase domain of the protein. They found the same mutation in 6 of 18 sporadic medullary thyroid carcinomas (155240). This conclusively demonstrates that MEN2A and MEN2B are related as allelic disorders; there is thus no justification for calling MEN2B MEN3. This identical point mutation in the catalytic core of the tyrosine kinase domain of RET was also found in association with both inherited and de novo MEN2B by Carlson et al. (1994) and Eng et al. (1994). The ATG-to-ACG mutation results in the substitution of threonine for methionine at codon 918 in the codon designation of Takahashi et al. (1988, 1989). Carlson et al. (1994) proposed that this amino acid replacement affects substrate interactions and results in oncogenic action by the RET protein. It is noteworthy that most mutations identified in cases of MEN2A and familial medullary thyroid carcinoma have been contained within the extracellular ligand-binding domain of the RET protooncogene and have resulted in nonconservative substitutions for 4 different cysteines. MEN2B has shown mainly noncysteine substitutions. The existence of polymorphic markers tightly linked to MEN2B and the fact that the M918T mutation accounts for almost all cases of MEN2B enabled Carlson et al. (1994) to determine unequivocally whether mutations occurred on the maternal or paternal chromosome. Strikingly, all 25 of the mutations they analyzed occurred in the paternal allele. Therefore, MEN2B can be added to the list of neoplastic diseases, which already includes Wilms tumor, bilateral retinoblastoma, osteosarcoma, embryonal rhabdomyosarcoma, and neurofibromatosis type I, for which the relevant genetic alteration occurs either predominantly or exclusively on the paternally derived chromosome. Carlson et al. (1994) also observed a paternal age effect. Santoro et al. (1995) demonstrated that this RET allele is a transforming gene in NIH 3T3 cells as a consequence of constitutive activation of the RET kinase. The mutation alters RET catalytic properties both quantitatively and qualitatively. Eng et al. (1995) analyzed 71 sporadic medullary thyroid carcinomas (68 primary tumors and 3 cell lines) for mutations in RET exons 10, 11, and 16. They found that 23% of sporadic MTC had RET codon 918 mutations (located in exon 16), while only 3% had exon 10 mutations and none had mutations in exon 11. They found no exon 16 mutations in MTC from 14 MEN2A cases. Thus, exon 10 and 11 mutations, commonly found in familial MTC and MEN2A, rarely occur in sporadic MTC; somatic mutation of RET codon 918 appears to play a role in the tumorigenesis of a significant minority of sporadic MTC but not in MEN2A tumors. In addition to their biologic interest, these findings may have clinical application in determining whether a case presenting with isolated MTC is truly sporadic or is part of an inherited cancer syndrome. The codon 918 mutation altered methionine (ATG) to threonine (ACG). In all instances in which germline DNA was available for analysis, it was found to be wildtype. This mutation was previously designated MET664THR. Eng et al. (1995) identified the M918T substitution in pheochromocytoma (171300) tumor tissue from 2 unrelated patients. The mutation was not identified in the germline of these patients. In MEN2A, mutations affecting cysteine residues in the extracellular domain of the receptor tyrosine kinase cause constitutive activation of the tyrosine kinase by the formation of disulfide-bonded homodimers. In MEN2B, only the met918-to-thr mutation in the tyrosine kinase domain has been identified. This mutation does not lead to dimer formation, but has been shown both biologically and biochemically to cause ligand-independent activation of the RET protein, but to a lesser extent than MEN2A mutations. Bongarzone et al. (1998) showed that the activity of the MEN2B RET mutation could be increased by stable dimerization of the receptor. Dimerization was achieved experimentally by constructing a double mutant receptor with a MEN2A mutation (cys634 to arg; 164761.0011) in addition to the MEN2B mutation, and by chronic exposure of the cells expressing the met918-to-thr mutation of RET to the RET ligand glial cell line-derived neurotrophic factor (GDNF; 600837). In both cases, full activation of the RET-MEN2B mutant protein, measured by in vitro transfection assays and biochemical parameters, was seen. These results indicated that the MEN2B phenotype could be influenced by the tissue distribution or concentration of RET ligand(s). (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: SCV001928067.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Pathogenic
(May 23, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Multiple endocrine neoplasia type 2B
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV004808391.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
|
Likely pathogenic
(Mar 10, 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: SCV000504363.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Oct 02, 2014)
|
no assertion criteria provided
Method: literature only
|
Thyroid tumor
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504364.1
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 2B
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000510477.1
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 1
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000510479.1
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: SCV000510481.1
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 4
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000510478.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Nov 03, 2006)
|
no assertion criteria provided
Method: clinical testing
|
Multiple endocrine neoplasia, type 2b
Affected status: yes
Allele origin:
germline
|
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000804923.1
First in ClinVar: Jun 30, 2018 Last updated: Jun 30, 2018 |
|
|
|
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: SCV001951822.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978545.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
|
|
Pathogenic
(Feb 21, 2024)
|
no assertion criteria provided
Method: clinical testing
|
RET-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004721813.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The RET c.2753T>C variant is predicted to result in the amino acid substitution p.Met918Thr. This variant has previously been reported to be causative for multiple … (more)
The RET c.2753T>C variant is predicted to result in the amino acid substitution p.Met918Thr. This variant has previously been reported to be causative for multiple endocrine neoplasia type 2B, medullary thyroid carcinoma, and pheochromocytoma (Carlson et al. 1994. PubMed ID: 7906417; Hedayati et al. 2011. PubMed ID : 21765987; de Cubas et al. 2013. PubMed ID : 23660872; http://www.arup.utah.edu/database/MEN2/). This variant was also shown in vitro to have transforming ability (Pasini et al. 1997. PubMed ID: 9242375; Cosci et al. 2011. PubMed ID: 21810974). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13919/). This variant is interpreted as pathogenic. (less)
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Comment:
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 7906417, 17540634, 8570194, 19169500, 22359510, 21810974, 23660872, 24336963, 21765987]
Comment:
Widely published variant reported to account for 95% of MEN2B cases. The best available variant frequency is uninformative because there are too few occurrences in population data. Found in multiple symptomatic patients. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Multiple de novo cases reported in the literature. In familial cases, variant segregates with disease.
Comment:
Variant summary: RET c.2753T>C (p.Met918Thr) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) 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 251618 control chromosomes. c.2753T>C has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2B (example, Carlson_1994, Elisei_2007, Hofstra_1994). These data indicate that the variant is very likely to be associated with disease. Multiple publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significant increase in tyrosine kinase activity resulting in a transforming activation of the RET proto-oncogene (example, Borrello_1995). Multiple 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
M918T is associated only with MEN2B phenotype.
Comment:
Most common RET variant reported in association with MEN2B (Carlson 1994, Eng 1996, Brauckhoff 2004, Wray 2008); Published functional studies demonstrate a damaging effect: increased transforming ability, cellular proliferation, and tyrosine phosphorylation (Pasini 1997, Cosci 2011); 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); This variant is associated with the following publications: (PMID: 10679286, 8570194, 30763276, 20516206, 15517484, 22359510, 10369718, 26843961, 23225389, 30660595, 18252215, 19826964, 11720239, 21765987, 9242375, 21810974, 7906417, 24336963, 23660265, 26294908, 23660872, 8918855, 7824936, 27807060, 27539324, 17963006, 29182461, 17540634, 19169500, 29396759, 16481266, 9541448, 18631354, 17576593, 17848262, 16808642, 26084817, 31510104, 29625052, 34308366, 33268590, 32561571, 8909322, 9706252, 33191720, 30624503, 32546069, 14633923)
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16715139, 9242375, 21810974]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7906417, 34629742, 29656518, 34881033, 25810047].
Comment:
PP4, PP5, PM1, PM2, PS3, PS4_moderate
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 918 of the RET protein (p.Met918Thr). This variant is present in population databases (rs74799832, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant multiple endocrine neoplasia type 2 (PMID: 7906417, 8918855, 16715139, 20516206, 27539324). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13919). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RET function (PMID: 8570194, 9242375, 16715139, 21810974). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.M918T pathogenic mutation (also known as c.2753T>C), located in coding exon 16 of the RET gene, results from a T to C substitution at nucleotide position 2753. The methionine at codon 918 is replaced by threonine, an amino acid with similar properties. This mutation is located in the catalytic core of the tyrosine kinase domain, within a highly conserved region of the RET protein. This mutation was first described in 58 individuals with a clinical diagnosis of multiple endocrine neoplasia type 2B (MEN2B) (Carlson KM et al. Proc. Natl. Acad. Sci. U.S.A. 1994;91(4):1579-83), and has since been well described in numerous other affected individuals (Choi S et al. PLoS Genet. 2012;8(2):e1002420; Hedayati M et al. J Thyroid Res. 2011;2011:264248; Smith V et al. Gut. 1999 Jul;45(1):143-6). In another study, this mutation was described in 95% (75/79) of MEN2B families (Eng C et al. JAMA 1996;276(19):1575-9). Per the revised American Thyroid Associated guidelines, individuals with alterations at codon 918 in the RET gene are at highest risk for MTC with recommended screenings and/or surgical interventions beginning in early childhood (Wells SA et al. Thyroid 2015 Jun; 25(6):567-610). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The RET c.2753T>C variant is predicted to result in the amino acid substitution p.Met918Thr. This variant has previously been reported to be causative for multiple endocrine neoplasia type 2B, medullary thyroid carcinoma, and pheochromocytoma (Carlson et al. 1994. PubMed ID: 7906417; Hedayati et al. 2011. PubMed ID : 21765987; de Cubas et al. 2013. PubMed ID : 23660872; http://www.arup.utah.edu/database/MEN2/). This variant was also shown in vitro to have transforming ability (Pasini et al. 1997. PubMed ID: 9242375; Cosci et al. 2011. PubMed ID: 21810974). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13919/). This variant is interpreted as 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.2753T>C, p.Met918Thr variant has been reported in multiple patients diagnosed with multiple endocrine neoplasia type 2b (Carlson 1994, Jindrichova 2004), co-segregated with affected family members, or occurred as a de novo alteration (Carlson 1994) and has been reported to confer high risk (Wells 2015). Functional characterization of the variant protein indicates an increase in basal auto-phosphorylation that is further enhanced upon growth factor stimulation, with altered target specificity compared to wildtype protein (Bongarzone 1998, Santoro 1995). The variant is listed in the dbSNP variant database (rs74799832), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Exome Aggregation Consortium). The methionine at residue 918 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic. References: Bongarzone I et al. Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation. Oncogene. 1998; 16(18):2295-301. Carlson K et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A. 1994; 91(4):1579-83. Jindrichova S et al. Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J Endocrinol. 2004; 183(2):257-65. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995; 267(5196):381-3. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015; 25(6):567-610.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 7906417, 17540634, 8570194, 19169500, 22359510, 21810974, 23660872, 24336963, 21765987]
Comment:
Widely published variant reported to account for 95% of MEN2B cases. The best available variant frequency is uninformative because there are too few occurrences in population data. Found in multiple symptomatic patients. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Multiple de novo cases reported in the literature. In familial cases, variant segregates with disease.
Comment:
Variant summary: RET c.2753T>C (p.Met918Thr) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) 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 251618 control chromosomes. c.2753T>C has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2B (example, Carlson_1994, Elisei_2007, Hofstra_1994). These data indicate that the variant is very likely to be associated with disease. Multiple publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significant increase in tyrosine kinase activity resulting in a transforming activation of the RET proto-oncogene (example, Borrello_1995). Multiple 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
M918T is associated only with MEN2B phenotype.
Comment:
Most common RET variant reported in association with MEN2B (Carlson 1994, Eng 1996, Brauckhoff 2004, Wray 2008); Published functional studies demonstrate a damaging effect: increased transforming ability, cellular proliferation, and tyrosine phosphorylation (Pasini 1997, Cosci 2011); 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); This variant is associated with the following publications: (PMID: 10679286, 8570194, 30763276, 20516206, 15517484, 22359510, 10369718, 26843961, 23225389, 30660595, 18252215, 19826964, 11720239, 21765987, 9242375, 21810974, 7906417, 24336963, 23660265, 26294908, 23660872, 8918855, 7824936, 27807060, 27539324, 17963006, 29182461, 17540634, 19169500, 29396759, 16481266, 9541448, 18631354, 17576593, 17848262, 16808642, 26084817, 31510104, 29625052, 34308366, 33268590, 32561571, 8909322, 9706252, 33191720, 30624503, 32546069, 14633923)
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16715139, 9242375, 21810974]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7906417, 34629742, 29656518, 34881033, 25810047].
Comment:
PP4, PP5, PM1, PM2, PS3, PS4_moderate
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 918 of the RET protein (p.Met918Thr). This variant is present in population databases (rs74799832, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant multiple endocrine neoplasia type 2 (PMID: 7906417, 8918855, 16715139, 20516206, 27539324). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13919). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RET function (PMID: 8570194, 9242375, 16715139, 21810974). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.M918T pathogenic mutation (also known as c.2753T>C), located in coding exon 16 of the RET gene, results from a T to C substitution at nucleotide position 2753. The methionine at codon 918 is replaced by threonine, an amino acid with similar properties. This mutation is located in the catalytic core of the tyrosine kinase domain, within a highly conserved region of the RET protein. This mutation was first described in 58 individuals with a clinical diagnosis of multiple endocrine neoplasia type 2B (MEN2B) (Carlson KM et al. Proc. Natl. Acad. Sci. U.S.A. 1994;91(4):1579-83), and has since been well described in numerous other affected individuals (Choi S et al. PLoS Genet. 2012;8(2):e1002420; Hedayati M et al. J Thyroid Res. 2011;2011:264248; Smith V et al. Gut. 1999 Jul;45(1):143-6). In another study, this mutation was described in 95% (75/79) of MEN2B families (Eng C et al. JAMA 1996;276(19):1575-9). Per the revised American Thyroid Associated guidelines, individuals with alterations at codon 918 in the RET gene are at highest risk for MTC with recommended screenings and/or surgical interventions beginning in early childhood (Wells SA et al. Thyroid 2015 Jun; 25(6):567-610). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The RET c.2753T>C variant is predicted to result in the amino acid substitution p.Met918Thr. This variant has previously been reported to be causative for multiple endocrine neoplasia type 2B, medullary thyroid carcinoma, and pheochromocytoma (Carlson et al. 1994. PubMed ID: 7906417; Hedayati et al. 2011. PubMed ID : 21765987; de Cubas et al. 2013. PubMed ID : 23660872; http://www.arup.utah.edu/database/MEN2/). This variant was also shown in vitro to have transforming ability (Pasini et al. 1997. PubMed ID: 9242375; Cosci et al. 2011. PubMed ID: 21810974). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13919/). This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Four cases of medullary thyroid carcinomas associated with multiple endocrine neoplasia 2B with rearranged during transfection codon M918T mutation in the same family. | Tanaka A | Molecular and clinical oncology | 2022 | PMID: 34881033 |
| Extra-endocrine phenotypes at infancy in multiple endocrine neoplasia type 2B: A case series of six Japanese patients. | Matsushita R | Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology | 2021 | PMID: 34629742 |
| Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations. | Elisei R | Genes | 2019 | PMID: 31510104 |
| Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study. | Castinetti F | The lancet. Diabetes & endocrinology | 2019 | PMID: 30660595 |
| Genotype-specific progression of hereditary medullary thyroid cancer. | Machens A | Human mutation | 2018 | PMID: 29656518 |
| Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
| M918V RET mutation causes familial medullary thyroid carcinoma: study of 8 affected kindreds. | Martins-Costa MC | Endocrine-related cancer | 2016 | PMID: 27807060 |
| Germline mutations and genotype-phenotype correlation in Asian Indian patients with pheochromocytoma and paraganglioma. | Pandit R | European journal of endocrinology | 2016 | PMID: 27539324 |
| A rare case of juvenile hypertension: coexistence of type 2 multiple endocrine neoplasia -related bilateral pheochromocytoma and reninoma in a young patient with ACE gene polymorphism. | Paragliola RM | BMC endocrine disorders | 2015 | PMID: 26084817 |
| 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 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| In silico profiling and structural insights of missense mutations in RET protein kinase domain by molecular dynamics and docking approach. | George Priya Doss C | Molecular bioSystems | 2014 | PMID: 24336963 |
| Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways. | de Cubas AA | Endocrine-related cancer | 2013 | PMID: 23660872 |
| AZD1480 blocks growth and tumorigenesis of RET- activated thyroid cancer cell lines. | Couto JP | PloS one | 2012 | PMID: 23056499 |
| Medullary thyroid cancer in a 9-week-old infant with familial MEN 2B: Implications for timing of prophylactic thyroidectomy. | Shankar RK | International journal of pediatric endocrinology | 2012 | PMID: 22992277 |
| Genetic alterations in a primary medullary thyroid carcinoma and its lymph node metastasis in a patient with 15 years follow-up. | González-Yebra B | Diagnostic pathology | 2012 | PMID: 22676344 |
| Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B. | Choi SK | PLoS genetics | 2012 | PMID: 22359510 |
| Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. | Wells SA Jr | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22025146 |
| Anti-tumor activity of motesanib in a medullary thyroid cancer model. | Coxon A | Journal of endocrinological investigation | 2012 | PMID: 21422803 |
| Mutational screening of RET, HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNB1 in medullary thyroid carcinoma. | Schulten HJ | Anticancer research | 2011 | PMID: 22199277 |
| 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 |
| The effects of four different tyrosine kinase inhibitors on medullary and papillary thyroid cancer cells. | Verbeek HH | The Journal of clinical endocrinology and metabolism | 2011 | PMID: 21470995 |
| Targeted therapies for thyroid tumors. | Sherman SI | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2011 | PMID: 21455200 |
| Single oligoarray-based detection of specific M918T mutation in RET oncogene in multiple endocrine neoplasia type 2B. | Pacheco-Rivera RA | Clinical and experimental medicine | 2011 | PMID: 21253810 |
| Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. | Carr LL | Clinical cancer research : an official journal of the American Association for Cancer Research | 2010 | PMID: 20847059 |
| 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 |
| Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. | Lam ET | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2010 | PMID: 20368568 |
| Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. | Wells SA Jr | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2010 | PMID: 20065189 |
| Phase II trial of sorafenib in metastatic thyroid cancer. | Kloos RT | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2009 | PMID: 19255327 |
| Early diagnosis of multiple endocrine neoplasia type 2B: a challenge for physicians. | Camacho CP | Arquivos brasileiros de endocrinologia e metabologia | 2008 | PMID: 19169500 |
| Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B: An exploratory analysis. | Brauckhoff M | Surgery | 2008 | PMID: 19041016 |
| Phase II trial of sorafenib in advanced thyroid cancer. | Gupta-Abramson V | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2008 | PMID: 18541894 |
| Renal aplasia in humans is associated with RET mutations. | Skinner MA | American journal of human genetics | 2008 | PMID: 18252215 |
| Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. | Elisei R | The Journal of clinical endocrinology and metabolism | 2008 | PMID: 18073307 |
| Failure to recognize multiple endocrine neoplasia 2B: more common than we think? | Wray CJ | Annals of surgical oncology | 2008 | PMID: 17963006 |
| Screening of RET gene mutations in multiple endocrine neoplasia type-2 using conformation sensitive gel electrophoresis (CSGE). | Santos MA | Arquivos brasileiros de endocrinologia e metabologia | 2007 | PMID: 18209889 |
| RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. | Elisei R | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17895320 |
| Multiple endocrine neoplasia type 2b associated with lichen nitidus. | Altaykan A | European journal of dermatology : EJD | 2007 | PMID: 17540634 |
| Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2B. | Gujral TS | Cancer research | 2006 | PMID: 17108110 |
| Evaluation of potential mechanisms underlying genotype-phenotype correlations in multiple endocrine neoplasia type 2. | Mise N | Oncogene | 2006 | PMID: 16715139 |
| The oncogenic activity of RET point mutants for follicular thyroid cells may account for the occurrence of papillary thyroid carcinoma in patients affected by familial medullary thyroid carcinoma. | Melillo RM | The American journal of pathology | 2004 | PMID: 15277225 |
| CGH alterations in medullary thyroid carcinomas in relation to the RET M918T mutation and clinical outcome. | Frisk T | International journal of oncology | 2001 | PMID: 11351254 |
| A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. | Iwashita T | Biochemical and biophysical research communications | 2000 | PMID: 10679286 |
| Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. | Iwashita T | Oncogene | 1999 | PMID: 10445857 |
| Intestinal ganglioneuromatosis and multiple endocrine neoplasia type 2B: implications for treatment. | Smith VV | Gut | 1999 | PMID: 10369718 |
| Genotype-phenotype correlation of patients with multiple endocrine neoplasia type 2 in Japan. | Egawa S | Japanese journal of clinical oncology | 1998 | PMID: 9839497 |
| Molecular biology of the MEN2 gene. | Santoro M | Journal of internal medicine | 1998 | PMID: 9681850 |
| Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation. | Bongarzone I | Oncogene | 1998 | PMID: 9620546 |
| Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain. | Pasini A | Oncogene | 1997 | PMID: 9242375 |
| 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 |
| Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease. | Eng C | The New England journal of medicine | 1996 | PMID: 8782503 |
| Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B. | Kitamura Y | Human molecular genetics | 1995 | PMID: 8595427 |
| RET activation by germline MEN2A and MEN2B mutations. | Borrello MG | Oncogene | 1995 | PMID: 8570194 |
| A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. | Eng C | Oncogene | 1995 | PMID: 7845675 |
| 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 |
| Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma. | Eng C | Genes, chromosomes & cancer | 1995 | PMID: 7536460 |
| Parent-of-origin effects in multiple endocrine neoplasia type 2B. | Carlson KM | American journal of human genetics | 1994 | PMID: 7977365 |
| Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. | Eng C | Human molecular genetics | 1994 | PMID: 7911697 |
| A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. | Hofstra RM | Nature | 1994 | PMID: 7906866 |
| Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. | Carlson KM | Proceedings of the National Academy of Sciences of the United States of America | 1994 | PMID: 7906417 |
| Isolation of ret proto-oncogene cDNA with an amino-terminal signal sequence. | Takahashi M | Oncogene | 1989 | PMID: 2660074 |
| Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. | Takahashi M | Oncogene | 1988 | PMID: 3078962 |
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| http://docm.genome.wustl.edu/variants/ENST00000340058:c.2753T>C | - | - | - | - |
| http://docm.genome.wustl.edu/variants/ENST00000355710:c.2753T>C | - | - | - | - |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RET | - | - | - | - |
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Text-mined citations for rs74799832 ...
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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.