ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2410G>T (p.Val804Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020975.6(RET):c.2410G>T (p.Val804Leu)
Variation ID: 13946 Accession: VCV000013946.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43119548 (GRCh38) [ NCBI UCSC ] 10: 43614996 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 8, 2017 May 1, 2024 Dec 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.2410G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Val804Leu missense NM_000323.2:c.2410G>T NP_000314.1:p.Val804Leu missense NM_001355216.2:c.1648G>T NP_001342145.1:p.Val550Leu missense NM_001406743.1:c.2410G>T NP_001393672.1:p.Val804Leu missense NM_001406744.1:c.2410G>T NP_001393673.1:p.Val804Leu missense NM_001406759.1:c.2410G>T NP_001393688.1:p.Val804Leu missense NM_001406760.1:c.2410G>T NP_001393689.1:p.Val804Leu missense NM_001406761.1:c.2281G>T NP_001393690.1:p.Val761Leu missense NM_001406762.1:c.2281G>T NP_001393691.1:p.Val761Leu missense NM_001406763.1:c.2275G>T NP_001393692.1:p.Val759Leu missense NM_001406764.1:c.2281G>T NP_001393693.1:p.Val761Leu missense NM_001406765.1:c.2275G>T NP_001393694.1:p.Val759Leu missense NM_001406766.1:c.2122G>T NP_001393695.1:p.Val708Leu missense NM_001406767.1:c.2122G>T NP_001393696.1:p.Val708Leu missense NM_001406768.1:c.2146G>T NP_001393697.1:p.Val716Leu missense NM_001406769.1:c.2014G>T NP_001393698.1:p.Val672Leu missense NM_001406770.1:c.2122G>T NP_001393699.1:p.Val708Leu missense NM_001406771.1:c.1972G>T NP_001393700.1:p.Val658Leu missense NM_001406772.1:c.2014G>T NP_001393701.1:p.Val672Leu missense NM_001406773.1:c.1972G>T NP_001393702.1:p.Val658Leu missense NM_001406774.1:c.1885G>T NP_001393703.1:p.Val629Leu missense NM_001406775.1:c.1684G>T NP_001393704.1:p.Val562Leu missense NM_001406776.1:c.1684G>T NP_001393705.1:p.Val562Leu missense NM_001406777.1:c.1684G>T NP_001393706.1:p.Val562Leu missense NM_001406778.1:c.1684G>T NP_001393707.1:p.Val562Leu missense NM_001406779.1:c.1513G>T NP_001393708.1:p.Val505Leu missense NM_001406780.1:c.1513G>T NP_001393709.1:p.Val505Leu missense NM_001406781.1:c.1513G>T NP_001393710.1:p.Val505Leu missense NM_001406782.1:c.1513G>T NP_001393711.1:p.Val505Leu missense NM_001406783.1:c.1384G>T NP_001393712.1:p.Val462Leu missense NM_001406784.1:c.1420G>T NP_001393713.1:p.Val474Leu missense NM_001406785.1:c.1393G>T NP_001393714.1:p.Val465Leu missense NM_001406786.1:c.1384G>T NP_001393715.1:p.Val462Leu missense NM_001406787.1:c.1378G>T NP_001393716.1:p.Val460Leu missense NM_001406788.1:c.1225G>T NP_001393717.1:p.Val409Leu missense NM_001406789.1:c.1225G>T NP_001393718.1:p.Val409Leu missense NM_001406790.1:c.1225G>T NP_001393719.1:p.Val409Leu missense NM_001406791.1:c.1105G>T NP_001393720.1:p.Val369Leu missense NM_001406792.1:c.961G>T NP_001393721.1:p.Val321Leu missense NM_001406793.1:c.961G>T NP_001393722.1:p.Val321Leu missense NM_001406794.1:c.961G>T NP_001393723.1:p.Val321Leu missense NM_020629.2:c.2410G>T NP_065680.1:p.Val804Leu missense NM_020630.7:c.2410G>T NP_065681.1:p.Val804Leu missense NC_000010.11:g.43119548G>T NC_000010.10:g.43614996G>T NG_007489.1:g.47480G>T LRG_518:g.47480G>T LRG_518t1:c.2410G>T LRG_518p1:p.Val804Leu LRG_518t2:c.2410G>T LRG_518p2:p.Val804Leu P07949:p.Val804Leu - Protein change
- V804L, V550L, V409L, V460L, V658L, V321L, V629L, V672L, V716L, V759L, V369L, V462L, V474L, V505L, V562L, V708L, V465L, V761L
- Other names
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- Canonical SPDI
- NC_000010.11:43119547:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3594 | 3716 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Jun 1, 2005 | RCV000014973.35 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 6, 2023 | RCV000021854.22 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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May 15, 2023 | RCV000354366.31 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 1, 2016 | RCV000487450.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 18, 2023 | RCV000596480.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 11, 2022 | RCV000561258.12 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial medullary thyroid carcinoma
Multiple endocrine neoplasia
Affected status: yes
Allele origin:
germline
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GenePathDx, GenePath diagnostics
Accession: SCV000574540.1
First in ClinVar: Apr 28, 2017 Last updated: Apr 28, 2017 |
Number of individuals with the variant: 1
|
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Pathogenic
(Mar 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000786135.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
|
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Pathogenic
(Nov 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000842755.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(Jan 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000705164.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Nov 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002522519.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
Comment:
PP1_strong, PP4, PP5, PM1, PM2, PM5, PS3_supporting
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Pathogenic
(Dec 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329834.8
First in ClinVar: Dec 06, 2016 Last updated: Dec 24, 2022 |
Comment:
Published functional studies demonstrate a damaging effect: increased transforming activity and autophosphorylation (Carlomagno et al., 2004; Iwashita et al., 1999; Kodama et al., 2014; Pasini … (more)
Published functional studies demonstrate a damaging effect: increased transforming activity and autophosphorylation (Carlomagno et al., 2004; Iwashita et al., 1999; Kodama et al., 2014; Pasini et al., 1997); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23811235, 7784092, 25637381, 23705946, 16507829, 26269449, 9067749, 23059849, 22162569, 15741265, 10235148, 9242375, 12694233, 20516206, 16532227, 27809725, 26678667, 16343097, 29590403, 31510104, 30624503, 33087929, 14633923, 26046350, 26247112, 11932300, 25349307, 15693160, 10445857, 15184865) (less)
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Pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002020785.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000824152.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 804 of the RET protein (p.Val804Leu). … (more)
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 804 of the RET protein (p.Val804Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with medullary thyroid carcinoma and/or pheochromocytoma (PMID: 7784092, 10235148, 15741265, 16343097, 18058472, 18062802, 19469690, 21626080, 25810047, 26269449). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13946). 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: 9242375, 16507829, 26046350). This variant disrupts the p.Val804 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8797874, 9452077, 10876191). 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
(May 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605022.4
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
The RET c.2410G>T; p.Val804Leu variant (rs79658334) has been reported in multiple individuals with familial medullary thyroid carcinoma (Lesueur 2005, Lombardo 2002, Patocs 2003) and multiple … (more)
The RET c.2410G>T; p.Val804Leu variant (rs79658334) has been reported in multiple individuals with familial medullary thyroid carcinoma (Lesueur 2005, Lombardo 2002, Patocs 2003) and multiple endocrine neoplasia type 2A (Learoyd 2005, Patocs 2003), segregating with affected individuals in the families (Learoyd 2005, Lombardo 2002, Patocs 2003). However, this variant was also found in some unaffected carriers in the pedigree, suggesting that it may have incomplete penetrance (Lombardo 2002, Patocs 2003). Functional characterization of the variant protein indicates autophosphorylation and activation of the kinase in the absence of growth factors, resulting in the increased phosphorylation of downstream targets and aberrant cell proliferation (Iwashita 1991, Pasini 1997). This variant is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 13946), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 804 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, the p.Val804Leu variant is considered to be pathogenic. References: Iwashita T et al. Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. Oncogene. 1991; 18(26):3919-22. Learoyd D et al. Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations. Clin Endocrinol (Oxf). 2005; 63(6):636-41. Lesueur F et al. Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients. J Clin Endocrinol Metab. 2005; 90(6):3454-7. Lombardo F et al. Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804. J Clin Endocrinol Metab. 2002; 87(4):1674-80. Pasini A et al. Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain. Oncogene. 1997; 15(4):393-402. Patocs A et al. Segregation of the V804L mutation and S836S polymorphism of exon 14 of the RET gene in an extended kindred with familial medullary thyroid cancer. Clin Genet. 2003; 63(3):219-23. (less)
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Pathogenic
(Nov 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004838669.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
The c.2410G>T (p.Val804Leu) variant in the RET gene results in an amino acid change at residue 804 from Valine to Leucine. This variant has been … (more)
The c.2410G>T (p.Val804Leu) variant in the RET gene results in an amino acid change at residue 804 from Valine to Leucine. This variant has been observed in individuals with medullary thyroid carcinoma (PMID: 7784092, 11932300, 12694233, 15741265, 16343097, 18058472, 18062802, 19469690, 21626080). It has also been observed to segregate with disease in related individuals (PMID:15741265, 11932300, 12694233). However, this variant was also found in some unaffected carriers in the pedigree, suggesting that it may have incomplete penetrance (PMID:11932300, 12694233). Functional studies demonstrated that this variant had a gain-of-function effect on increased level of tyrosine phosphorylation compared to wildtype in one RET isoform and aberrant cell proliferation (PMID: 10445857, 9242375). This variant is rarely present in population databases (gnomAD). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (REVEL score ?0.7). A variant with distinct nucleotide change c.2410G>C, resulting in the same amino acid replacement p.Val804Leu, has been classified as pathogenic (ClinVar ID:38613). Another variant affecting the same amino acid, c.2410G>A (p.Val804Met), have also been classified as pathogenic (ClinVar ID:37102). Therefore, this variant c.2410G>T (p.Val804Leu) in RET is interpreted as pathogenic. (less)
Number of individuals with the variant: 3
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Pathogenic
(Apr 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018495.1
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: 9242375]. This variant has been reported in multiple individuals with clinical … (more)
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9242375]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20497437, 16343097, 11932300, 25810047]. (less)
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Pathogenic
(Apr 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV004357248.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with leucine at codon 804 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces valine with leucine at codon 804 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant resulted in intermediate level of transforming activity on ex vivo transfected cells (PMID: 9242375, 10445857) and to confer resistance to select kinase inhibitors (PMID: 26046350, 26046350). This variant has been reported in dozens of heterozygous individuals affected with medullary thyroid cancer (PMID: 7784092, 10235148, 11932300, 12694233, 15741265, 20516206, 21626080) and one homozygous carrier affected with medullary thyroid cancer and pheochromocytoma (PMID: 15741265). This variant is also reported to segregate with disease in multiple families (PMID: 10235148, 11932300). This variant is reported to confer moderate risk for medullary thyroid cancer (PMID: 25810047). This variant has been identified in 1/232600 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Mar 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000674843.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.V804L pathogenic mutation (also known as c.2410G>T), located in coding exon 14 of the RET gene, results from a G to T substitution at … (more)
The p.V804L pathogenic mutation (also known as c.2410G>T), located in coding exon 14 of the RET gene, results from a G to T substitution at nucleotide position 2410. The valine at codon 804 is replaced by leucine, an amino acid with highly similar properties. This alteration occurs in the ATP binding pocket of the tyrosine-kinase domain of the RET receptor, and has been reported as a pathogenic mutation associated with both FMTC and MEN2A (Toledo SP et al. Clinics (Sao Paulo) 2006 Feb; 61(1):59-70; Raue F et al. Fam. Cancer 2010 Sep; 9(3):449-57). Additionally, this alteration was detected in conjunction with a second RET alteration, pVal648Ile, in another individual with features of MEN2A, including pheochromocytoma and medullary thyroid cancer (Verrienti A et al. Endocr Pract, 2015 Nov;21:1248-54). Functional studies demonstrate that p.V804L transfected cells exhibit an increase in the level of tyrosine phosphorylation compared to wildtype in one RET isoform, supporting its oncogenic potential (Pasini A et al. Oncogene 1997 Jul;15(4):393-402). In addition, expression studies demonstrate that p.V804L has a low transforming activity compared to other RET mutations. Transforming activity is associated with clinical phenotype; mutations with low transforming activity are associated with a milder MEN2/FMTC phenotype compared to mutations with high transforming activity that are associated with a more severe MEN2B phenotype (Iwashita T et al. Oncogene 1999 Jul;18(26):3919-22). The American Thyroid Association Guidelines Task Force has provided recommendations for individuals with RET gene mutations (Kloos et al. Thyroid. 2009 June; 19(6):565-612). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jun 01, 2005)
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no assertion criteria provided
Method: literature only
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THYROID CARCINOMA, FAMILIAL MEDULLARY
Affected status: not provided
Allele origin:
unknown
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OMIM
Accession: SCV000035229.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2017 |
Comment on evidence:
A codon 804 mutation in the RET gene leading to the substitution of valine by leucine (V804L) was first identified in 2 unrelated French families … (more)
A codon 804 mutation in the RET gene leading to the substitution of valine by leucine (V804L) was first identified in 2 unrelated French families with familial medullary thyroid carcinoma (MTC; 155240) (Farndon et al., 1986; Bolino et al., 1995). Lombardo et al. (2002) studied 61 heterozygotes harboring the germline V804L mutation of the RET protooncogene in 5 independent families, including one reported by Bolino et al. (1995). A total of 31 subjects underwent surgery. Histology identified C-cell hyperplasia in 30 cases, isolated in 12 and associated with MTC in 18. Six patients with MTC had lymph node metastases. Among the 14 patients with basal detectable calcitonin (114130) level, 12 had MTC and 2 had isolated C cell hyperplasia. In most individuals carrying the V804L RET mutation, C cell disease displayed late onset and an indolent course; a pentagastrin test was negative in the majority of heterozygotes during the first 2 decades and was positive in only half of them during the third and fourth decades of life. The authors concluded that in these gene carriers, surgery may be postponed to the fourth decade of life or until the pentagastrin stimulation test becomes positive. They also suggested that their data be confirmed on a larger series of V804L carriers, but that it may offer a balanced strategy to keep under control and prevent development of the full disease phenotype. Ruiz et al. (2001), among others, had found a germline variant, ser836 to ser (S836S) (due to a nucleotide change in exon 14 of the RET gene which does not change the amino acid), that occurred at a significantly higher frequency in patients with sporadic MTC than in control subjects without sporadic MTC. Based on this observation, it had been postulated that the S836S polymorphism reacts as a low-penetrance allele in MTC and, perhaps, in FMTC families with a small number of affected members who have no typical RET gene mutations. In an extended Hungarian FMTC kindred whose members had a germline V804L mutation and a germline S836S polymorphism in separate alleles in exon 14 of the RET gene, Patocs et al. (2003) analyzed the clinical associations. The observations suggested that the coexistence of the V804L mutation and the S836S polymorphism in separate alleles did not aggravate the relatively low-risk disease phenotype characteristic in most patients with codon 804 mutations of exon 14 of the RET gene. Three of the family members who had the V804L mutation and 1 member who could not be tested for mutation were operated on for nonmetastatic MTC, while 1 member with MTC who had the V804L mutation refused surgery. In all patients affected with MTC, the disease developed relatively late in life and never caused death. Lesueur et al. (2005) compared the clinical data and age of diagnosis among 3 patients homozygous for either V804L or V804M (see 164761.0043), 6 other heterozygous cases from the same populations, and other homozygous and heterozygous subjects reported previously. The data were consistent with a model in which codon 804 mutations have low penetrance, the developing of medullary thyroid carcinoma being associated with a second germline or somatic mutation. The authors concluded that the activity and (in the case of somatic mutations) timing of these other genetic alterations in the RET gene may explain the wide clinical variability associated with germline mutations at codon 804. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Distribution of RET Mutations in Multiple Endocrine Neoplasia 2 in Denmark 1994-2014: A Nationwide Study. | Mathiesen JS | Thyroid : official journal of the American Thyroid Association | 2017 | PMID: 27809725 |
Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients. | Currás-Freixes M | Journal of medical genetics | 2015 | PMID: 26269449 |
A NOVEL DOUBLE MUTATION VAL648ILE AND VAL804LEU OF RET PROTO-ONCOGENE IN MULTIPLE ENDOCRINE NEOPLASIA TYPE 2. | Verrienti A | Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists | 2015 | PMID: 26247112 |
Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase. | Moccia M | PloS one | 2015 | PMID: 26046350 |
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 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
The rare intracellular RET mutation p.S891A in a Chinese Han family with familial medullary thyroid carcinoma. | Qi XP | Journal of biosciences | 2014 | PMID: 24845513 |
Patient affected by neurofibromatosis type 1 and thyroid C-cell hyperplasia harboring pathogenic germ-line mutations in both NF1 and RET genes. | Ercolino T | Gene | 2014 | PMID: 24361808 |
Simultaneous medullary and papillary thyroid cancer: a novel entity? | Machens A | Annals of surgical oncology | 2012 | PMID: 21626080 |
RET codon 804 mutations in multiple endocrine neoplasia 2: genotype-phenotype correlations and implications in clinical management. | Mukherjee S | Clinical genetics | 2011 | PMID: 20497437 |
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 |
Update multiple endocrine neoplasia type 2. | Raue F | Familial cancer | 2010 | PMID: 20087666 |
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 |
Familial prevalence and age of RET germline mutations: implications for screening. | Machens A | Clinical endocrinology | 2008 | PMID: 18062802 |
The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their unaffected kindred's from Central Poland. | Paszko Z | Cancer investigation | 2007 | PMID: 18058472 |
New era: prophylactic surgery for patients with multiple endocrine neoplasia-2a. | Gosnell JE | ANZ journal of surgery | 2006 | PMID: 16813623 |
Occurrence of the Cys611Tyr mutation and a novel Arg886Trp substitution in the RET proto-oncogene in multiple endocrine neoplasia type 2 families and sporadic medullary thyroid carcinoma cases originating from the central region of Portugal. | Prazeres HJ | Clinical endocrinology | 2006 | PMID: 16712668 |
Impact of RET proto-oncogene analysis on the clinical management of multiple endocrine neoplasia type 2. | Toledo SP | Clinics (Sao Paulo, Brazil) | 2006 | PMID: 16532227 |
BAY 43-9006 inhibition of oncogenic RET mutants. | Carlomagno F | Journal of the National Cancer Institute | 2006 | PMID: 16507829 |
Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations. | Learoyd DL | Clinical endocrinology | 2005 | PMID: 16343097 |
Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients. | Lesueur F | The Journal of clinical endocrinology and metabolism | 2005 | PMID: 15741265 |
Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. | Carlomagno F | Oncogene | 2004 | PMID: 15184865 |
Segregation of the V804L mutation and S836S polymorphism of exon 14 of the RET gene in an extended kindred with familial medullary thyroid cancer. | Patócs A | Clinical genetics | 2003 | PMID: 12694233 |
Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804. | Lombardo F | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 11932300 |
Germline sequence variant S836S in the RET proto-oncogene is associated with low level predisposition to sporadic medullary thyroid carcinoma in the Spanish population. | Ruiz A | Clinical endocrinology | 2001 | PMID: 11589684 |
Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation. | Feldman GL | Surgery | 2000 | PMID: 10876191 |
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 |
Adrenal and extra-adrenal pheochromocytomas in a family with germline RET V804L mutation. | Nilsson O | JAMA | 1999 | PMID: 10235148 |
A GTG to ATG novel point mutation at codon 804 in exon 14 of the RET proto-oncogene in two families affected by familial medullary thyroid carcinoma. | Fattoruso O | Human mutation | 1998 | PMID: 9452077 |
A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. | Hofstra RM | The Journal of clinical endocrinology and metabolism | 1997 | PMID: 9398735 |
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 |
RET mutations in exons 13 and 14 of FMTC patients. | Bolino A | Oncogene | 1995 | PMID: 7784092 |
Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. | Farndon JR | The British journal of surgery | 1986 | PMID: 3697657 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RET | - | - | - | - |
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Text-mined citations for rs79658334 ...
HelpRecord last updated Nov 03, 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.