ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2410G>A (p.Val804Met)
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
-
NM_020975.6(RET):c.2410G>A (p.Val804Met)
Variation ID: 37102 Accession: VCV000037102.85
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q11.21 10: 43119548 (GRCh38) [ NCBI UCSC ] 10: 43614996 (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 Dec 6, 2014 Oct 8, 2024 Jul 31, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_020975.6:c.2410G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Val804Met missense NM_000323.2:c.2410G>A NP_000314.1:p.Val804Met missense NM_001355216.2:c.1648G>A NP_001342145.1:p.Val550Met missense NM_001406743.1:c.2410G>A NP_001393672.1:p.Val804Met missense NM_001406744.1:c.2410G>A NP_001393673.1:p.Val804Met missense NM_001406759.1:c.2410G>A NP_001393688.1:p.Val804Met missense NM_001406760.1:c.2410G>A NP_001393689.1:p.Val804Met missense NM_001406761.1:c.2281G>A NP_001393690.1:p.Val761Met missense NM_001406762.1:c.2281G>A NP_001393691.1:p.Val761Met missense NM_001406763.1:c.2275G>A NP_001393692.1:p.Val759Met missense NM_001406764.1:c.2281G>A NP_001393693.1:p.Val761Met missense NM_001406765.1:c.2275G>A NP_001393694.1:p.Val759Met missense NM_001406766.1:c.2122G>A NP_001393695.1:p.Val708Met missense NM_001406767.1:c.2122G>A NP_001393696.1:p.Val708Met missense NM_001406768.1:c.2146G>A NP_001393697.1:p.Val716Met missense NM_001406769.1:c.2014G>A NP_001393698.1:p.Val672Met missense NM_001406770.1:c.2122G>A NP_001393699.1:p.Val708Met missense NM_001406771.1:c.1972G>A NP_001393700.1:p.Val658Met missense NM_001406772.1:c.2014G>A NP_001393701.1:p.Val672Met missense NM_001406773.1:c.1972G>A NP_001393702.1:p.Val658Met missense NM_001406774.1:c.1885G>A NP_001393703.1:p.Val629Met missense NM_001406775.1:c.1684G>A NP_001393704.1:p.Val562Met missense NM_001406776.1:c.1684G>A NP_001393705.1:p.Val562Met missense NM_001406777.1:c.1684G>A NP_001393706.1:p.Val562Met missense NM_001406778.1:c.1684G>A NP_001393707.1:p.Val562Met missense NM_001406779.1:c.1513G>A NP_001393708.1:p.Val505Met missense NM_001406780.1:c.1513G>A NP_001393709.1:p.Val505Met missense NM_001406781.1:c.1513G>A NP_001393710.1:p.Val505Met missense NM_001406782.1:c.1513G>A NP_001393711.1:p.Val505Met missense NM_001406783.1:c.1384G>A NP_001393712.1:p.Val462Met missense NM_001406784.1:c.1420G>A NP_001393713.1:p.Val474Met missense NM_001406785.1:c.1393G>A NP_001393714.1:p.Val465Met missense NM_001406786.1:c.1384G>A NP_001393715.1:p.Val462Met missense NM_001406787.1:c.1378G>A NP_001393716.1:p.Val460Met missense NM_001406788.1:c.1225G>A NP_001393717.1:p.Val409Met missense NM_001406789.1:c.1225G>A NP_001393718.1:p.Val409Met missense NM_001406790.1:c.1225G>A NP_001393719.1:p.Val409Met missense NM_001406791.1:c.1105G>A NP_001393720.1:p.Val369Met missense NM_001406792.1:c.961G>A NP_001393721.1:p.Val321Met missense NM_001406793.1:c.961G>A NP_001393722.1:p.Val321Met missense NM_001406794.1:c.961G>A NP_001393723.1:p.Val321Met missense NM_020629.2:c.2410G>A NP_065680.1:p.Val804Met missense NM_020630.7:c.2410G>A NP_065681.1:p.Val804Met missense NM_020975.5:c.2410G>A NC_000010.11:g.43119548G>A NC_000010.10:g.43614996G>A NG_007489.1:g.47480G>A LRG_518:g.47480G>A LRG_518t1:c.2410G>A LRG_518p1:p.Val804Met LRG_518t2:c.2410G>A LRG_518p2:p.Val804Met P07949:p.Val804Met - Protein change
- V804M, V550M, V321M, V460M, V672M, V759M, V369M, V409M, V462M, V658M, V708M, V465M, V505M, V629M, V716M, V474M, V562M, V761M
- Other names
- -
- Canonical SPDI
- NC_000010.11:43119547:G:A
-
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.
Trans-Omics for Precision Medicine (TOPMed) 0.00010
The Genome Aggregation Database (gnomAD) 0.00022
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 |
3592 | 3714 |
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 (14) |
criteria provided, multiple submitters, no conflicts
|
Jul 31, 2024 | RCV000182584.67 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 13, 2024 | RCV000210181.20 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV000148773.30 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 18, 2017 | RCV000515232.10 | |
Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Oct 13, 2023 | RCV000499191.20 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV001804750.15 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2022 | RCV003153308.9 | |
RET-related disorder
|
Likely pathogenic (2) |
criteria provided, single submitter
|
Oct 4, 2022 | RCV004528141.3 |
Pathogenic (1) |
criteria provided, single submitter
|
Mar 7, 2024 | RCV003460494.2 | |
Pathogenic (1) |
criteria provided, single submitter
|
Apr 14, 2023 | RCV000586783.10 |
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
(Aug 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002069070.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the RET gene demonstrated a sequence change, c.2410G>A, in exon 14 that results in an amino acid change, p.Val804Met. This sequence … (more)
DNA sequence analysis of the RET gene demonstrated a sequence change, c.2410G>A, in exon 14 that results in an amino acid change, p.Val804Met. This sequence change is a well-described pathogenic variant in the RET gene that has been reported in multiple families with medullary thyroid carcinoma (PMID: 7784092, 8797874, 9452077, 25440022, 10876191, 17895320, 11114642, 19958926). The American Thyroid Association categorizes this as a moderate-risk variant meaning that the risk for aggressive medullary thyroid cancer may be reduced in comparison with other pathogenic variants in the RET gene (PMID: 25810047). This sequence change has been described in the gnomAD database with a frequency of 0.02% in the Latino/Admixed American subpopulation (dbSNP rs79658334). The p.Val804Met change affects a highly conserved amino acid residue located in a domain of the RET protein that is known to be functional. The p.Val804Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Experimental studies have shown that this pathogenic sequence change affects the normal function of the RET protein (PMID: 20039896 21711375). Collectively these evidences indicate this variant is pathogenic. (less)
|
|
Pathogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760465.5
First in ClinVar: Dec 17, 2022 Last updated: Aug 04, 2024 |
|
|
Pathogenic
(Oct 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249002.25
First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024 |
Comment:
RET: PP1:Strong, PS3, PS4:Moderate
Number of individuals with the variant: 8
|
|
Pathogenic
(Aug 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial medullary thyroid carcinoma
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581664.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PM1, PM5, PM2_SUP, PP3
|
Number of individuals with the variant: 3
Sex: male
|
|
Pathogenic
(Oct 04, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002529975.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The RET c.2410G>A (p.V804M) variant has been reported in heterozygosity in numerous individuals with multiple endocrine neoplasia type 2 (MEN2A) and familial medullary thyroid carcinoma … (more)
The RET c.2410G>A (p.V804M) variant has been reported in heterozygosity in numerous individuals with multiple endocrine neoplasia type 2 (MEN2A) and familial medullary thyroid carcinoma (MTC) (PMID: 10876191, 20516206, 24617864, 29590403, 31510104, 33167350). This variant is the most frequent RET mutation in the Italian population (PMID: 31510104). The p.V804M variant is generally not associated with pheochromocytoma, parathyroid adenoma or hyperparathyroidism, and the American Thyroid Association considers this variant a moderate risk for MTC (PMID: 25810047). One study estimated that the cumulative lifetime risk for MTC in individuals carrying this variant is 17% by age 40, 31% by age 50, 67% by age 60 and 87% by age 70 (PMID: 24617864), while one recent study estimated only 4% (95% CI, 0.9% to 8%) lifetime risk of MTC (PMID: 29590403). The variant has also been seen in individuals with papillary thyroid cancer, pheochromocytomas, and primary hyperparathyroidism (PMID: 31510104). This variant was observed in 7/34510 chromosomes in the Latino population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 37102). In silico tools suggest the impact of the variant on protein function is deleterious, which is supported by functional studies which show that the variant effects cell viability, migration, and tyrosine kinase activity of the protein (PMID: 21711375). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Sep 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000234936.14
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: increased transforming activity (Cosci et al., 2011); In silico analysis supports that this missense variant does not alter … (more)
Published functional studies demonstrate a damaging effect: increased transforming activity (Cosci et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15693160, 24336963, 20516206, 28951487, 17466010, 11732489, 24361808, 19958926, 20494215, 23468374, 8797874, 21810974, 20369307, 25501606, 10826520, 16507829, 24466223, 10876191, 11788682, 15184865, 27099842, 27814560, 27809725, 25903693, 28647780, 15386323, 28125075, 26556299, 19445625, 16955009, 16343097, 31159747, 9452077, 29590403, 30093976, 30936199, 31510104, 30763276, 29625052, 31447099, 23341727, 33615670, 31589614, 33361738, 11932300, 30624503, 30787465, 33087929) (less)
|
|
Pathogenic
(Apr 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
MEN2 phenotype: Unclassified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699459.2
First in ClinVar: Mar 17, 2018 Last updated: Jun 03, 2023 |
Comment:
Variant summary: RET c.2410G>A (p.Val804Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: RET c.2410G>A (p.Val804Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 232600 control chromosomes (gnomAD). This variant has been reported to have a variable penetrance as the most frequently altered codon in multiple patients with features of FMTC (Familial Medullary Thyroid Cancer) and CCH (C-cell hyperplasia). c.2410G>A has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2, C-cell hyperplasia, and adrenocortical carcinoma (examples: Fink_1996, Miyauchi_1999, Ercolino_2014, Raygada_2020, and Alzahrani_2022). At-least one publication reported this variant as a de novo occurrence (Miyauchi_1999). These data indicate that the variant is very likely to be associated with disease. A pathogenic co-occurrence (MSH2 c.211+1G>T) have been reported in at-least one report (Raygada_RET_MG_2020). Multiple publications report experimental evidence evaluating an impact on protein function. These studies showed the variant moderately increased transforming activity (Cosci_2011) and increased kinase activity compared to WT (Plaza-Menacho_2011). Other variants affecting the same amino acid are reported as associated with Thyroid cancer and Multiple endocrine neoplasia 2 in HGMD. Twenty-six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Oct 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002587114.1
First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022 |
Comment:
_x000D_ Criteria applied: PS4, PM5_STR, PS2_MOD, PS3_SUP
|
|
Pathogenic
(Apr 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial medullary thyroid carcinoma
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV003927229.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
This RET variant (rs79658334) is rare (<0.1%) in a large population dataset (gnomAD: 36/263944 total alleles; 0.014%; no homozygotes) and has been reported in ClinVar. … (more)
This RET variant (rs79658334) is rare (<0.1%) in a large population dataset (gnomAD: 36/263944 total alleles; 0.014%; no homozygotes) and has been reported in ClinVar. This variant has been shown to segregate with medullary thyroid carcinoma (MTC) in several families with reduced penetrance compared to other pathogenic variants in the RET gene. This variant is defined by the American Thyroid Association as a level A variant, which represents the lowest risk group for developing MTC. It is estimated that the cumulative lifetime risk for MTC in individuals harboring this variant is 31% by age 50, 67% by age 60 and 87% by age 70, although penetrance has also been estimated to be as low as 4%. In vitro functional studies demonstrate this substitution leads to increased cellular proliferation and increased tyrosine kinase activity. This is supported by structural analysis that indicates the alteration changes the conformation of the ATP binding pocket, making it more permissive for binding ATP, and thus enhancing RET activation. We consider c.2410G>A to be pathogenic. (less)
|
|
Likely pathogenic
(Oct 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: no
Allele origin:
paternal
|
Institute of Human Genetics, Heidelberg University
Accession: SCV004100313.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Sex: male
|
|
Pathogenic
(Nov 20, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266128.1
First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016 |
Number of individuals with the variant: 1
Clinical Features:
breast cancer (present)
Age: 40-49 years
|
|
Pathogenic
(May 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000840056.1
First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018 |
Comment:
This c.2410G>A (p.Val804Met) variant in the RET gene has been reported in multiple publications [PMID 8797874, 20369307, 21810974, 24361808, 23468374, 23341727, 11732489, 24336963, 19958926, 20494215]. … (more)
This c.2410G>A (p.Val804Met) variant in the RET gene has been reported in multiple publications [PMID 8797874, 20369307, 21810974, 24361808, 23468374, 23341727, 11732489, 24336963, 19958926, 20494215]. This variant was reported in patients and segregating in multiple families with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma [PMID 8797874, 23468374, 23341727, 20369307, 19958926, 20494215]. In vitro analysis showed that this variant affect the function of the RET protein [PMID 21810974]. A different nucleotide change (c.2410G>C), affecting the same amino acid (p.Val804Leu) has also been reported in a patient with multiple endocrine neoplasia 2 [PMID 14718397]. This variant is highly conserved and while not validated for clinical use, computer-based algorithms predict this p.Val804Met change to be deleterious. This variant has been observed in 13 heterozygous individuals in the ExAC database (http://exac.broadinstitute.org/variant/10-43614996-G-A). It is thus classified as pathogenic. (less)
|
|
Pathogenic
(Aug 02, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000344435.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
Pathogenic
(May 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711346.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
The p.Val804Met variant in RET has been reported in > 6 probands with multiple e ndocrine neoplasia type 2 (MEN2), occurring de novo in at … (more)
The p.Val804Met variant in RET has been reported in > 6 probands with multiple e ndocrine neoplasia type 2 (MEN2), occurring de novo in at least one of these ind ividuals, and segregated with disease in over 25 affected relatives from 5 affec ted families (for examples, see Kasprzak 2001, Shifrin 2009, Shifrin 2010, Nakao 2013, Kihara 2014, Ercolino 2014). The majority of individuals with this varian t have familial medullary thyroid carcinoma, although at least 2 individuals wer e diagnosed with MEN2B. In vitro functional studies provide some evidence that t his variant may impact protein function (Machens 2011, Castellone 2010). The p.V al804Met variant has been classified by the American Thyroid Association as impa rting a moderate risk to developing aggressive medullary thyroid carcinoma (Well s 2015). It has also been reported by other clinical laboratories in ClinVar (Va riation ID #37102). In addition, this variant has been identified in 21/116790 o f European chromosomes by the Genome Aggregation Consortium (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs79658334). In summary, this variant meets criteri a to be classified as pathogenic for MEN2 in an autosomal dominant manner based on presence in multiple affected individuals and segregation studies. (less)
Number of individuals with the variant: 5
|
|
Likely pathogenic
(Jan 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ovarian cancer
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University
Accession: SCV003843741.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
|
|
Pathogenic
(Feb 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774396.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 06, 2024 |
Comment:
In the published literature, the c.2410G>A variant has been noted to be enriched in MEN2 and FMTC patients in published patient screens (PMID: 15741265 (2005), … (more)
In the published literature, the c.2410G>A variant has been noted to be enriched in MEN2 and FMTC patients in published patient screens (PMID: 15741265 (2005), 17316110 (2007), 17895320 (2007), 25624014 (2015), 26758973 (2016)). Increased kinase activity, altered substrate specificity, and resistance to some drugs have been observed in the published literature (PMID: 21454698 (2011)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000290546.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 804 of the RET protein (p.Val804Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 804 of the RET protein (p.Val804Met). This variant is present in population databases (rs79658334, gnomAD 0.02%). This variant has been reported to segregate with medullary thyroid carcinoma (MTC) in several families with reduced penetrance compared to other pathogenic variants in the RET gene (PMID: 8797874, 9452077, 10876191, 25501606, 19958926, 11114642, 12019403, 17895320, 25440022). The cumulative lifetime risk for MTC in individuals harboring this variant has been calculated to be 17% by age 40, 31% by age 50, 67% by age 60, and 87% by age 70 (PMID: 24617864). Genotype-phenotype correlations have been described (PMID: 25810047). ClinVar contains an entry for this variant (Variation ID: 37102). 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: 15184865, 20039896, 21711375). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Feb 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002817215.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant is statistically … (more)
The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant is statistically significantly enriched in affected patients as compared to ethnically matched controls. The American Thyroid Association has placed this variant into the ATA-MOD category, which includes the former levels A and B, for having a moderate risk of developing aggressive medullary thyroid carcinoma (MTC; see PMID: 25810047). This variant associates with disease in multiple families with medullary thyroid cancer and appears to occur de novo in one individual with MEN2B. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 21454698) (less)
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial medullary thyroid carcinoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004239131.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 804 of the RET protein (p.Val804Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 804 of the RET protein (p.Val804Met). This variant is present in population databases (rs79658334, gnomAD 0.02%). This variant has been reported to segregate with medullary thyroid carcinoma (MTC) in several families with reduced penetrance compared to other pathogenic variants in the RET gene (PMID: 8797874, 9452077, 10876191, 25501606, 19958926, 11114642, 12019403, 17895320, 25440022). The cumulative lifetime risk for MTC in individuals harboring this variant has been calculated to be 17% by age 40, 31% by age 50, 67% by age 60, and 87% by age 70 (PMID: 24617864). Genotype-phenotype correlations have been described (PMID: 25810047). ClinVar contains an entry for this variant (Variation ID: 37102). In silico analysis supports that this missense variant does not alter protein structure/function. Experimental studies have shown that this missense change affects RET function (PMID: 15184865, 20039896, 21711375).The American Thyroid Association has designated alterations at this codon occurring without additional RET mutations as moderate risk mutations (Wells SA et al. Thyroid. 2015 Jun;25:567-610). For these reasons, this variant has been classified as Pathogenic. Pathogenic mutations in the RET gene cause Medullary thyroid carcinoma (MIM# 155240). (less)
Age: 50-59 years
Sex: male
|
|
Pathogenic
(Mar 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hirschsprung disease, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004208634.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
Pathogenic
(May 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hirschsprung disease, susceptibility to, 1
Familial medullary thyroid carcinoma Multiple endocrine neoplasia type 2B Pheochromocytoma Multiple endocrine neoplasia type 2A Renal hypodysplasia/aplasia 1 Central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611313.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
|
|
Likely pathogenic
(Jan 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821780.2
First in ClinVar: Oct 10, 2018 Last updated: Mar 25, 2020 |
Comment:
This sequence change replaces Valine with Methionine at codon 804 of the RET protein. The valine residue is highly conserved among species in the Protein … (more)
This sequence change replaces Valine with Methionine at codon 804 of the RET protein. The valine residue is highly conserved among species in the Protein kinase domain of the protein. There is a small physicochemical difference between valine and methionine (Grantham Score 21). This variant has been described in several families with multiple endocrine neoplasia type 2 and medullary thyroid carcinoma (MTC) (PMID 8797874, 23468374, 9452077, 10876191, 25501606). This variant is listed in population databases at a very low frequency (rs79658334, ExAC 0.03%). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may have a deleterious impact on protein function. Moreover, this prediction has been confirmed experimentally (PMID: 20039896,21711375,) .The mutation database ClinVar contains multiple entries for this variant (Variation ID:37102). (less)
|
|
Pathogenic
(Jul 21, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450236.1
First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020 |
Number of individuals with the variant: 5
|
|
Pathogenic
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2a
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000838401.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
|
Pathogenic
(Apr 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605023.7
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
The RET c.2410G>A; p.Val804Met variant (rs79658334) has been described in individuals affected with multiple endocrine neoplasia type 2 (MEN2), and has shown to segregate with … (more)
The RET c.2410G>A; p.Val804Met variant (rs79658334) has been described in individuals affected with multiple endocrine neoplasia type 2 (MEN2), and has shown to segregate with disease but with reduced penetrance compared to different pathogenic RET variants (Basaran 2015, Choi 2013, Elisei 2007, Fattoruso 1998, Feldman 2000, Fink 1996, Romei 2015). It is generally not associated with pheochromocytoma, parathyroid adenoma or hyperparathyroidism, and the American Thyroid Association describes individuals with this variant as having a moderate risk for medullary thyroid cancer (MTC) (Wells 2015). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 37102) and is observed in the general population at an overall frequency of 0.014% (36/259772 alleles) in the Genome Aggregation Database. It is estimated that the cumulative lifetime risk for MTC in individuals harboring this variant is 31% by age 50, 67% by age 60 and 87% by age 70 (Rich 2014), although penetrance has also been estimated to be as low as 4% (Loveday 2018). The valine at codon 804 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.716). Additionally, in vitro functional studies demonstrate increased cellular proliferation and tyrosine kinase activity, as well as a conferred resistance to selective kinase inhibitors (Carlomagno 2004, Castellone 2010, Cosci 2011, Machens 2011). Based on available information, this variant is considered pathogenic. References: Basaran M et al. Characterization of V804M-mutated RET proto-oncogene associated with familial medullary thyroid cancer, report of the largest Turkish family. J Endocrinol Invest. 2015 May;38(5):541-6. PMID: 25501606 Carlomango F et al. Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene. 2004 Aug 12;23(36):6056-63. PMID: 15184865 Castellone M et al. A novel de novo germ-line V292M mutation in the extracellular region of RET in a patient with phaeochromocytoma and medullary thyroid carcinoma: functional characterization. Clin Endocrinol (Oxf). 2010 Oct;73(4):529-34. PMID: 20039896 Choi Y et al. A Case of medullary thyroid carcinoma with de novo V804M RET germline mutation. J Korean Med Sci. 2013; 28(1):156-9. PMID: 23341727 Cosci B et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer. 2011; 18(5):603-12. PMID: 21810974 Elisei R et al. RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab. 2007; 92(12):4725-9. PMID: 17895320 Fattoruso O et al. 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. Hum Mutat. 1998; Suppl 1:S167-71. PMID: 9452077 Feldman G et al. Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation. Surgery. 2000; 128(1):93-8. PMID: 10876191 Fink M et al. Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. "Study Group Multiple Endocrine Neoplasia Austria (SMENA)". Int J Cancer. 1996; 69(4):312-6. PMID: 8797874 Loveday C et al. p.Val804Met, the most frequent pathogenic mutation in RET, confers a very low lifetime risk of medullary thyroid cancer. J Clin Endocrinol Metab. 2018 Mar 23. PMID: 29590403 Machens A et al. Germline RET sequence variation I852M and occult medullary thyroid cancer: harmless polymorphism or causative mutation? Clin Endocrinol (Oxf). 2011 Dec;75(6):801-5. PMID: 21711375 Rich T et al. Prevalence by age and predictors of medullary thyroid cancer in patients with lower risk germline RET proto-oncogene mutations. Thyroid. 2014 Jul;24(7):1096-106. PMID: 24617864 Romei C et al. Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer? Clin Endocrinol (Oxf). 2015; 82(6):892-9. PMID: 25440022 Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. PMID: 25810047 (less)
|
|
Pathogenic
(May 23, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000677731.2
First in ClinVar: Aug 21, 2017 Last updated: Dec 24, 2022 |
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Familial medullary thyroid carcinoma
Affected status: yes
Allele origin:
de novo
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002053758.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
|
|
Pathogenic
(Jul 14, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020789.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Likely pathogenic
(Oct 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
RET-related disease
Affected status: unknown
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV004183391.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PM5 moderated, PM6 moderated, PP3 supporting
Geographic origin: Brazil
|
|
Pathogenic
(Jan 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004357247.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with methionine 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 methionine 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 the variant resulted in intermediate level of transforming activity on transfected cells in vitro (PMID: 21810974) and an intermediate increase in kinase activity over wild-type RET (PMID: 20039896), as well as selective resistance to tyrosine kinase inhibitors (PMID: 15184865). This variant has been reported in dozens of heterozygous individuals affected with medullary thyroid cancer (PMID: 8797874, 9452077, 10876191, 11114642, 15741265, 23341727, 24361808, 33167350) that is rarely accompanied by hyperparathyroidism and/or pheochromocytoma (PMID: 15386323, 17466010, 31510104) and 3 homozygous carriers affected with medullary thyroid cancer, including one with pheochromocytoma (PMID: 12019403, 15741265). This variant has been reported to confer moderate risks for medullary thyroid cancer (PMID: 25810047). Missense variants at codon 804, p.Val804Leu and p.Val804Met, have lower penetrance than other RET missense variants with cumulative medullary thyroid cancer penetrance probability by age from 3% at 30y, 17% at 40y, 31% at 50y, 67% at 60y, to 87% at 70y (PMID: 24617864). This variant also has been reported to segregate with disease in affected pedigrees (PMID: 9452077, 10826520, 10876191, 11114642, 12019403, 15386323, 17466010, 21134561, 24361808, 25501606). This variant has been identified in 36/263944 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
Pathogenic
(Apr 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004043759.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 24560924, 21810974, 21711375, 20039896, 15184865]. This variant has been reported in … (more)
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 24560924, 21810974, 21711375, 20039896, 15184865]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15386323, 34637071, 25501606, 21134561, 10876191, 11114642, 29590403, 25810047, 20497437]. (less)
|
|
Pathogenic
(Jan 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198058.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
Pathogenic
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004822637.1
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)
|
Comment:
This missense variant replaces valine with methionine 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 methionine 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 the variant resulted in intermediate level of transforming activity on transfected cells in vitro (PMID: 21810974) and an intermediate increase in kinase activity over wild-type RET (PMID: 20039896), as well as selective resistance to tyrosine kinase inhibitors (PMID: 15184865). This variant has been reported in dozens of heterozygous individuals affected with medullary thyroid cancer (PMID: 8797874, 9452077, 10876191, 11114642, 15741265, 23341727, 24361808, 33167350) that is rarely accompanied by hyperparathyroidism and/or pheochromocytoma (PMID: 15386323, 17466010, 31510104) and 3 homozygous carriers affected with medullary thyroid cancer, including one with pheochromocytoma (PMID: 12019403, 15741265). This variant has been reported to confer moderate risks for medullary thyroid cancer (PMID: 25810047). Missense variants at codon 804, p.Val804Leu and p.Val804Met, have lower penetrance than other RET missense variants with cumulative medullary thyroid cancer penetrance probability by age from 3% at 30y, 17% at 40y, 31% at 50y, 67% at 60y, to 87% at 70y (PMID: 24617864). This variant also has been reported to segregate with disease in affected pedigrees (PMID: 9452077, 10826520, 10876191, 11114642, 12019403, 15386323, 17466010, 21134561, 24361808, 25501606). This variant has been identified in 36/263944 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 20
|
|
Pathogenic
(Jul 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002522518.2
First in ClinVar: Jun 05, 2022 Last updated: Jan 26, 2024 |
Comment:
PP1_strong, PP4, PP5, PM6, PS4_moderate
Number of individuals with the variant: 10
|
|
Pathogenic
(Jun 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000674764.7
First in ClinVar: Mar 20, 2016 Last updated: Aug 11, 2024 |
Comment:
The p.V804M mutation (also known as c.2410G>A), located in coding exon 14 of the RET gene, results from a G to A substitution at nucleotide … (more)
The p.V804M mutation (also known as c.2410G>A), located in coding exon 14 of the RET gene, results from a G to A substitution at nucleotide position 2410. The valine at codon 804 is replaced by methionine, an amino acid with highly similar properties. This mutation has been described in an Austrian family with familial medullary thyroid carcinoma (FMTC) and was present in both affected and unaffected family members (Fink M et al. Int. J. Cancer. 1996 Aug;69:312-6). This alteration has also been reported as a confirmed de novo mutation in the setting of new MTC disease in a family (Choi YS et al. J. Korean Med. Sci. 2013 Jan;28:156-9; Nakao KT et al. Head Neck. 2013 Dec;35:E363-8). This alteration has been reported in individuals with homozygous state (Lesueur F et al. J Clin Endocrinol Metab, 2005 Jun;90:3454-7; Lecube A et al. Surgery, 2002 May;131:509-14). A few studies have suggested that in addition to the association with MTC, mutations at codon 804 may be associated with papillary thyroid carcinoma (Brauckhoff M et al. Langenbeck's Arch Surg. 2002 Oct;387:201-3; Shifrin AL et al. Surgery. 2009 Dec;146:998-1005; Basaran MN et al. J. Endocrinol. Invest. 2015 May;38:541-6). The p.V804M mutation has also been reported in families with pheochromocytomas (Recasens M et al. Clin. Endocrinol. (Oxf). 2007 Jul;67:29-33). In vitro analyses demonstrated that cells transfected with the p.V804M alteration produced an intermediate number of focus formation units and an intermediate number of colonies when compared to wild-type, but did not show any significant difference from wild-type with respect to the proliferation rate (Cosci B et al. Endocr. Relat. Cancer. 2011 Sep;18:603-12). Additional in vitro analysis shows that the RET p.V804M alteration has a marked increase in kinase activity over wild-type (Machens A et al. Clin. Endocrinol. (Oxf). 2011 Dec;75:801-5). This is supported by structural analysis that indicates the alteration changes the conformation of the ATP binding pocket, making it more permissive for binding ATP, and thus enhancing RET activation (George Priya Doss C et al. Mol Biosyst. 2014 Mar;10:421-36). Disease expression of mutations at codon 804 have been shown to be highly variable, even within the same family (Feldman GL et al. Surgery. 2000 Jul;128:93-8; Frohnauer MK and Decker RA. Surgery. 2000 Dec;128:1052-7). The American Thyroid Association has designated alterations at this codon occurring without additional RET mutations as moderate risk mutations (Wells SA et al. Thyroid. 2015 Jun;25:567-610). Based on the available evidence, p.V804M is classified as a pathogenic mutation with moderate risk. (less)
|
|
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: SCV001930996.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
Pathogenic
(Aug 02, 2024)
|
no assertion criteria provided
Method: clinical testing
|
RET-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000807027.3
First in ClinVar: Sep 13, 2018 Last updated: Oct 08, 2024 |
Comment:
The RET c.2410G>A variant is predicted to result in the amino acid substitution p.Val804Met. This variant has been reported in individuals with medullary thyroid carcinoma … (more)
The RET c.2410G>A variant is predicted to result in the amino acid substitution p.Val804Met. This variant has been reported in individuals with medullary thyroid carcinoma (reported as c804 in Frohnauer and Decker. 2000. PubMed ID:11114642; Choi et al. 2013. PubMed ID: 23341727; Kasprzak et al. 2001. PubMed ID: 11732489; Rothberg et al. 2009. PubMed ID: 19445625). However, some reports have described this variant as having low penetrance and only causing carcinoma in the homozygous state (Lecube et al. 2002. PubMed ID 12019403; Lesueur et al. 2005. PubMed ID 15741265). Functional studies show the p.Val804Met variant results in slightly higher growth and transformation rates compared to wild type RET (Cosci et al. 2011. PubMed ID: 21810974). Notably, an alternate substitution of this amino acid (p.Val804Leu) has also been reported in individuals with thyroid cancer (Kruckeberg and Thibodeau. 2004. PubMed ID 14718397; Table S1 in Currás-Freixes et al. 2015. PubMed ID 26269449; Pasini et al. 1997. PubMed ID 9242375). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. This variant is classified as pathogenic/likely pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37102/). Based on the available information, this variant is interpreted as pathogenic. (less)
|
|
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: SCV001959743.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Pathogenic
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Multiple endocrine neoplasia 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190510.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
|
|
Likely pathogenic
(Jul 13, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000590903.1
First in ClinVar: Aug 21, 2017 Last updated: Aug 21, 2017 |
Comment:
This variant has been previously reported in patients from various ethnic origins with MTC and the variant has been shown to co-segregate with the disease … (more)
This variant has been previously reported in patients from various ethnic origins with MTC and the variant has been shown to co-segregate with the disease by Romei C et al in 2015, Basaran MN et al in 2015, Fink M et al in 1996 and Fattoruso et al in 1998.This variant has been reported in the dbSNP database with identification number rs79658334 and in ExAC database with the allele frequency of 0.025%. In the Clin Var database , the clinical significance of this variant has been reported as pathogenic (RCV000148773.3) with respect to MEN2. In silico prediction tools(SIFT, LRT, MutationTaster, PolyPhen-2 and FATHMM) suggests that this variant is probably damaging to protein function. (less)
Clinical Features:
Medullary thyroid carcinoma (present)
Age: 20-29 years
Sex: female
Ethnicity/Population group: Hindu/Rajasthan
Geographic origin: India
Method: The library was prepared using the TruSight One kit from Illumina. The protocol requires 50ng of input DNA. The library Is prepared using the transposase based Nextera technology with single indexing. Three libraries, 500ng of each, were pooled and captured using target specific biotinylated probes. Post-capture, the libraries were cleaned up to remove excess probes and untargeted DNA using Streptavidin beads. The enriched library was loaded on MiSeq and equenced using 2 x 150 V3 sequencing kit. Clinically relevant mutations were annotated using published variants in literature and a set of variant databases including ClinVar, OMIM, GWAS, HGMD and SWISSVar.
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Multiple Endocrine Neoplasia Type 2. | Adam MP | - | 2023 | PMID: 20301434 |
Controversy on the management of patients carrying RET p.V804M mutation. | Alzahrani AS | Endocrine | 2022 | PMID: 34637071 |
Case report of adrenocortical carcinoma associated with double germline mutations in MSH2 and RET. | Raygada M | American journal of medical genetics. Part A | 2021 | PMID: 33615670 |
Homozygosity for the pathogenic RET hotspot variant p.Cys634Trp: A consanguineous family with MEN2A. | Schirwani S | European journal of medical genetics | 2021 | PMID: 33450337 |
Results and Clinical Interpretation of Germline RET Analysis in a Series of Patients with Medullary Thyroid Carcinoma: The Challenge of the Variants of Uncertain Significance. | Innella G | Cancers | 2020 | PMID: 33167350 |
Emergence and Targeting of Acquired and Hereditary Resistance to Multikinase RET Inhibition in Patients With RET-Altered Cancer. | Wirth LJ | JCO precision oncology | 2019 | PMID: 32923848 |
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 |
p.Val804Met, the Most Frequent Pathogenic Mutation in RET, Confers a Very Low Lifetime Risk of Medullary Thyroid Cancer. | Loveday C | The Journal of clinical endocrinology and metabolism | 2018 | PMID: 29590403 |
Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study. | Ghazani AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28125075 |
How to Assess the Clinical Relevance of Novel RET Missense Variants in the Absence of Functional Studies? | Karrasch T | European thyroid journal | 2016 | PMID: 27099842 |
Distribution of RET Mutations and Evaluation of Treatment Approaches in Hereditary Medullary Thyroid Carcinoma in Turkey. | Aydoğan Bİ | Journal of clinical research in pediatric endocrinology | 2016 | PMID: 26758973 |
Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase. | Moccia M | PloS one | 2015 | PMID: 26046350 |
C-Cell Neoplasia in Asymptomatic Carriers of RET Mutation in Extracellular Cysteine-Rich and Intracellular Tyrosine Kinase Domain. | Abi-Raad R | Human pathology | 2015 | PMID: 26033033 |
Papillary thyroid carcinoma and multiple endocrine neoplasia type 2. | Febrero B | Journal of endocrinological investigation | 2015 | PMID: 25903693 |
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 |
Genetic screening of patients with medullary thyroid cancer in a referral center in Greece during the past two decades. | Sarika HL | European journal of endocrinology | 2015 | PMID: 25624014 |
Characterization of V804M-mutated RET proto-oncogene associated with familial medullary thyroid cancer, report of the largest Turkish family. | Basaran MN | Journal of endocrinological investigation | 2015 | PMID: 25501606 |
Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer? | Romei C | Clinical endocrinology | 2015 | PMID: 25440022 |
Tandem Germline RET Mutations in a Family Pathogenetic for Multiple Endocrine Neoplasia 2B, Confirmed by a Natural Experiment. | Kihara M | European thyroid journal | 2014 | PMID: 25759805 |
Alectinib shows potent antitumor activity against RET-rearranged non-small cell lung cancer. | Kodama T | Molecular cancer therapeutics | 2014 | PMID: 25349307 |
Prevalence by age and predictors of medullary thyroid cancer in patients with lower risk germline RET proto-oncogene mutations. | Rich TA | Thyroid : official journal of the American Thyroid Association | 2014 | PMID: 24617864 |
Oncogenic RET kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans. | Plaza-Menacho I | Molecular cell | 2014 | PMID: 24560924 |
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 |
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 |
The optimal range of RET mutations to be tested: European comments to the guidelines of the American Thyroid Association. | Fugazzola L | Thyroid research | 2013 | PMID: 23514012 |
Novel tandem germline RET proto-oncogene mutations in a patient with multiple endocrine neoplasia type 2B: report of a case and a literature review of tandem RET mutations with in silico analysis. | Nakao KT | Head & neck | 2013 | PMID: 23468374 |
A Case of medullary thyroid carcinoma with de novo V804M RET germline mutation. | Choi YS | Journal of Korean medical science | 2013 | PMID: 23341727 |
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 |
Germline RET sequence variation I852M and occult medullary thyroid cancer: harmless polymorphism or causative mutation? | Machens A | Clinical endocrinology | 2011 | PMID: 21711375 |
Focal adhesion kinase (FAK) binds RET kinase via its FERM domain, priming a direct and reciprocal RET-FAK transactivation mechanism. | Plaza-Menacho I | The Journal of biological chemistry | 2011 | PMID: 21454698 |
Molecular analysis of the RET proto-oncogene key exons in patients with medullary thyroid carcinoma: a comprehensive study of the Iranian population. | Alvandi E | Thyroid : official journal of the American Thyroid Association | 2011 | PMID: 21309721 |
RET codon 804 mutations in multiple endocrine neoplasia 2: genotype-phenotype correlations and implications in clinical management. | Mukherjee S | Clinical genetics | 2011 | PMID: 20497437 |
Single nucleotide polymorphisms act as modifiers and correlate with the development of medullary and simultaneous medullary/papillary thyroid carcinomas in 2 large, non-related families with the RET V804M proto-oncogene mutation. | Shifrin AL | Surgery | 2010 | PMID: 21134561 |
One hundred and seven member family with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: Is this a new syndrome-MEN 2C? | Shifrin AL | Surgery | 2010 | PMID: 20719260 |
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 |
Simultaneous medullary and papillary thyroid carcinomas in carriers of the V804M RET germline mutation-a spurious association? | Machens A | Surgery | 2010 | PMID: 20494215 |
Synchronous metastatic medullary and papillary thyroid carcinomas in a patient with germline RET mutation: case report, molecular analysis, and implications for pathogenesis. | Griffith C | Endocrine pathology | 2010 | PMID: 20369307 |
Kindred with prominent corneal nerves associated with a mutation in codon 804 of RET on chromosome 10q11. | Ong DS | Archives of ophthalmology (Chicago, Ill. : 1960) | 2010 | PMID: 20142552 |
A novel de novo germ-line V292M mutation in the extracellular region of RET in a patient with phaeochromocytoma and medullary thyroid carcinoma: functional characterization. | Castellone MD | Clinical endocrinology | 2010 | PMID: 20039896 |
One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: is this a new syndrome--MEN 2C? | Shifrin AL | Surgery | 2009 | PMID: 19958926 |
Familial medullary thyroid carcinoma associated with cutaneous lichen amyloidosis. | Rothberg AE | Thyroid : official journal of the American Thyroid Association | 2009 | PMID: 19445625 |
Uncommon association of germline mutations of RET proto-oncogene and CDKN2A gene. | Foppiani L | European journal of endocrinology | 2008 | PMID: 18299477 |
Familial prevalence and age of RET germline mutations: implications for screening. | Machens A | Clinical endocrinology | 2008 | PMID: 18062802 |
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 |
Sorafenib functions to potently suppress RET tyrosine kinase activity by direct enzymatic inhibition and promoting RET lysosomal degradation independent of proteasomal targeting. | Plaza-Menacho I | The Journal of biological chemistry | 2007 | PMID: 17664273 |
Asymptomatic bilateral adrenal pheochromocytoma in a patient with a germline V804M mutation in the RET proto-oncogene. | Recasens M | Clinical endocrinology | 2007 | PMID: 17466010 |
RET proto-oncogene in Sardinia: V804M is the most frequent mutation and may be associated with FMTC/MEN-2A phenotype. | Pinna G | Thyroid : official journal of the American Thyroid Association | 2007 | PMID: 17316110 |
RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. | Cranston AN | Cancer research | 2006 | PMID: 17047083 |
Inhibition of RET tyrosine kinase by SU5416. | Mologni L | Journal of molecular endocrinology | 2006 | PMID: 17032739 |
Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype. | Frank-Raue K | European journal of endocrinology | 2006 | PMID: 16868135 |
Genotype-phenotype correlations in Hungarian patients with hereditary medullary thyroid cancer. | Patocs A | Wiener klinische Wochenschrift | 2006 | PMID: 16865647 |
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 |
Germline RET V804M mutation associated with multiple endocrine neoplasia type 2A. | Gibelin H | The British journal of surgery | 2004 | PMID: 15386323 |
Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. | Carlomagno F | Oncogene | 2004 | PMID: 15184865 |
Primary hyperparathyroidism, C-cell hyperplasia and papillary thyroid carcinoma in a patient with RET germline polymorphism S836S. | Brauckhoff M | Langenbeck's archives of surgery | 2002 | PMID: 12410354 |
Papillary thyroid carcinoma in patients with RET proto-oncogene germline mutation. | Brauckhoff M | Thyroid : official journal of the American Thyroid Association | 2002 | PMID: 12193298 |
V804M RET mutation and familial medullary thyroid carcinoma: report of a large family with expression of the disease only in the homozygous gene carriers. | Lecube A | Surgery | 2002 | PMID: 12019403 |
Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918. | Menko FH | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 11788682 |
Familial medullary thyroid carcinoma and prominent corneal nerves associated with the germline V804M and V778I mutations on the same allele of RET. | Kasprzak L | Journal of medical genetics | 2001 | PMID: 11732489 |
Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties. | Machens A | The Journal of clinical endocrinology and metabolism | 2001 | PMID: 11238493 |
Update on the MEN 2A c804 RET mutation: is prophylactic thyroidectomy indicated? | Frohnauer MK | Surgery | 2000 | PMID: 11114642 |
Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation. | Feldman GL | Surgery | 2000 | PMID: 10876191 |
A RET double mutation in the germline of a kindred with FMTC. | Bartsch DK | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2000 | PMID: 10826520 |
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 |
Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. | Miyauchi A | Japanese journal of cancer research : Gann | 1999 | PMID: 10076558 |
Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. | Dralle H | World journal of surgery | 1998 | PMID: 9606292 |
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 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RET | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs79658334 ...
HelpRecord last updated Oct 08, 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.