NM_020975.6(RET):c.2410G>A (p.Val804Met) AND Multiple endocrine neoplasia, type 2
- Germline classification:
- Pathogenic (5 submissions)
- Last evaluated:
- Jan 31, 2024
- Review status:
- 2 stars out of maximum of 4 starscriteria provided, multiple submitters, no conflicts
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000148773.30
Allele description [Variation Report for NM_020975.6(RET):c.2410G>A (p.Val804Met)]
NM_020975.6(RET):c.2410G>A (p.Val804Met)
- Gene:
- RET:ret proto-oncogene [Gene - OMIM - HGNC]
- Variant type:
- single nucleotide variant
- Cytogenetic location:
- 10q11.21
- Genomic location:
- Preferred name:
- NM_020975.6(RET):c.2410G>A (p.Val804Met)
- HGVS:
- NC_000010.11:g.43119548G>A
- NG_007489.1:g.47480G>A
- NM_000323.2:c.2410G>A
- NM_001355216.2:c.1648G>A
- NM_001406743.1:c.2410G>A
- NM_001406744.1:c.2410G>A
- NM_001406759.1:c.2410G>A
- NM_001406760.1:c.2410G>A
- NM_001406761.1:c.2281G>A
- NM_001406762.1:c.2281G>A
- NM_001406763.1:c.2275G>A
- NM_001406764.1:c.2281G>A
- NM_001406765.1:c.2275G>A
- NM_001406766.1:c.2122G>A
- NM_001406767.1:c.2122G>A
- NM_001406768.1:c.2146G>A
- NM_001406769.1:c.2014G>A
- NM_001406770.1:c.2122G>A
- NM_001406771.1:c.1972G>A
- NM_001406772.1:c.2014G>A
- NM_001406773.1:c.1972G>A
- NM_001406774.1:c.1885G>A
- NM_001406775.1:c.1684G>A
- NM_001406776.1:c.1684G>A
- NM_001406777.1:c.1684G>A
- NM_001406778.1:c.1684G>A
- NM_001406779.1:c.1513G>A
- NM_001406780.1:c.1513G>A
- NM_001406781.1:c.1513G>A
- NM_001406782.1:c.1513G>A
- NM_001406783.1:c.1384G>A
- NM_001406784.1:c.1420G>A
- NM_001406785.1:c.1393G>A
- NM_001406786.1:c.1384G>A
- NM_001406787.1:c.1378G>A
- NM_001406788.1:c.1225G>A
- NM_001406789.1:c.1225G>A
- NM_001406790.1:c.1225G>A
- NM_001406791.1:c.1105G>A
- NM_001406792.1:c.961G>A
- NM_001406793.1:c.961G>A
- NM_001406794.1:c.961G>A
- NM_020629.2:c.2410G>A
- NM_020630.7:c.2410G>A
- NM_020975.6:c.2410G>AMANE SELECT
- NP_000314.1:p.Val804Met
- NP_001342145.1:p.Val550Met
- NP_001342145.1:p.Val550Met
- NP_001393672.1:p.Val804Met
- NP_001393673.1:p.Val804Met
- NP_001393688.1:p.Val804Met
- NP_001393689.1:p.Val804Met
- NP_001393690.1:p.Val761Met
- NP_001393691.1:p.Val761Met
- NP_001393692.1:p.Val759Met
- NP_001393693.1:p.Val761Met
- NP_001393694.1:p.Val759Met
- NP_001393695.1:p.Val708Met
- NP_001393696.1:p.Val708Met
- NP_001393697.1:p.Val716Met
- NP_001393698.1:p.Val672Met
- NP_001393699.1:p.Val708Met
- NP_001393700.1:p.Val658Met
- NP_001393701.1:p.Val672Met
- NP_001393702.1:p.Val658Met
- NP_001393703.1:p.Val629Met
- NP_001393704.1:p.Val562Met
- NP_001393705.1:p.Val562Met
- NP_001393706.1:p.Val562Met
- NP_001393707.1:p.Val562Met
- NP_001393708.1:p.Val505Met
- NP_001393709.1:p.Val505Met
- NP_001393710.1:p.Val505Met
- NP_001393711.1:p.Val505Met
- NP_001393712.1:p.Val462Met
- NP_001393713.1:p.Val474Met
- NP_001393714.1:p.Val465Met
- NP_001393715.1:p.Val462Met
- NP_001393716.1:p.Val460Met
- NP_001393717.1:p.Val409Met
- NP_001393718.1:p.Val409Met
- NP_001393719.1:p.Val409Met
- NP_001393720.1:p.Val369Met
- NP_001393721.1:p.Val321Met
- NP_001393722.1:p.Val321Met
- NP_001393723.1:p.Val321Met
- NP_065680.1:p.Val804Met
- NP_065681.1:p.Val804Met
- NP_065681.1:p.Val804Met
- NP_065681.1:p.Val804Met
- NP_066124.1:p.Val804Met
- NP_066124.1:p.Val804Met
- LRG_518t1:c.2410G>A
- LRG_518t2:c.2410G>A
- LRG_518:g.47480G>A
- LRG_518p1:p.Val804Met
- LRG_518p2:p.Val804Met
- NC_000010.10:g.43614996G>A
- NM_001355216.1:c.1648G>A
- NM_020630.4:c.2410G>A
- NM_020630.6:c.2410G>A
- NM_020975.4:c.2410G>A
- NM_020975.5:c.2410G>A
- P07949:p.Val804Met
This HGVS expression did not pass validation- Protein change:
- V321M; VAL804MET
- Links:
- UniProtKB: P07949#VAR_006337; OMIM: 164761.0043; dbSNP: rs79658334
- NCBI 1000 Genomes Browser:
- rs79658334
- Molecular consequence:
- NM_000323.2:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001355216.2:c.1648G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406743.1:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406744.1:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406759.1:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406760.1:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406761.1:c.2281G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406762.1:c.2281G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406763.1:c.2275G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406764.1:c.2281G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406765.1:c.2275G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406766.1:c.2122G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406767.1:c.2122G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406768.1:c.2146G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406769.1:c.2014G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406770.1:c.2122G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406771.1:c.1972G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406772.1:c.2014G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406773.1:c.1972G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406774.1:c.1885G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406775.1:c.1684G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406776.1:c.1684G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406777.1:c.1684G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406778.1:c.1684G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406779.1:c.1513G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406780.1:c.1513G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406781.1:c.1513G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406782.1:c.1513G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406783.1:c.1384G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406784.1:c.1420G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406785.1:c.1393G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406786.1:c.1384G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406787.1:c.1378G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406788.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406789.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406790.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406791.1:c.1105G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406792.1:c.961G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406793.1:c.961G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406794.1:c.961G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_020629.2:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_020630.7:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_020975.6:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- Observations:
- 5
Condition(s)
- Name:
- Multiple endocrine neoplasia, type 2 (MEN2)
- Identifiers:
- MONDO: MONDO:0019003; MedGen: C4048306
-
gamma-sarcoglycan isoform X1 [Daktulosphaira vitifoliae]
gamma-sarcoglycan isoform X1 [Daktulosphaira vitifoliae]gi|2304382728|ref|XP_050527328.1|Protein
-
MULTISPECIES: thiazole biosynthesis adenylyltransferase ThiF [Enterobacter]
MULTISPECIES: thiazole biosynthesis adenylyltransferase ThiF [Enterobacter]gi|695625786|ref|WP_032608234.1|Protein
-
MULTISPECIES: uroporphyrinogen decarboxylase [Enterobacter]
MULTISPECIES: uroporphyrinogen decarboxylase [Enterobacter]gi|550794718|ref|WP_022650209.1|Protein
-
dnaJ homolog subfamily B member 3-like isoform X2 [Argiope bruennichi]
dnaJ homolog subfamily B member 3-like isoform X2 [Argiope bruennichi]gi|2504415520|ref|XP_055939109.1|Protein
-
PREDICTED: Mus musculus NCK-associated protein 5 (Nckap5), transcript variant X1...
PREDICTED: Mus musculus NCK-associated protein 5 (Nckap5), transcript variant X19, mRNAgi|1907068037|ref|XM_036163207.1|Nucleotide
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See more...Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000190510 | CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation | no assertion criteria provided | Pathogenic (Jun 1, 2014) | germline | research | |
| SCV000290546 | Labcorp Genetics (formerly Invitae), Labcorp | criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) | Pathogenic (Jan 31, 2024) | germline | clinical testing | |
| SCV000711346 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | criteria provided, single submitter (LMM Criteria) | Pathogenic (May 24, 2017) | germline | clinical testing | |
| SCV004357247 | Color Diagnostics, LLC DBA Color Health | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jan 3, 2024) | germline | clinical testing | |
| SCV004822637 | All of Us Research Program, National Institutes of Health | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jan 8, 2024) | germline | clinical testing |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | germline | not provided | 5 | 5 | not provided | not provided | not provided | clinical testing |
| not provided | germline | unknown | 20 | not provided | not provided | 108544 | not provided | clinical testing, research |
Citations
PubMed
Elisei R, Romei C, Cosci B, Agate L, Bottici V, Molinaro E, Sculli M, Miccoli P, Basolo F, Grasso L, Pacini F, Pinchera A.
J Clin Endocrinol Metab. 2007 Dec;92(12):4725-9. Epub 2007 Sep 25.
- PMID:
- 17895320
Romei C, Tacito A, Molinaro E, Agate L, Bottici V, Viola D, Matrone A, Biagini A, Casella F, Ciampi R, Materazzi G, Miccoli P, Torregrossa L, Ugolini C, Basolo F, Vitti P, Elisei R.
Clin Endocrinol (Oxf). 2015 Jun;82(6):892-9. doi: 10.1111/cen.12686. Epub 2014 Dec 29.
- PMID:
- 25440022
Details of each submission
From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190510.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | research | not provided |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Labcorp Genetics (formerly Invitae), Labcorp, SCV000290546.11
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (15) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711346.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 5 | not provided | not provided | clinical testing | PubMed (10) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | not provided | not provided | not provided | not provided | 5 | not provided | 5 | not provided | |
From Color Diagnostics, LLC DBA Color Health, SCV004357247.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (21) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From All of Us Research Program, National Institutes of Health, SCV004822637.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 20 | not provided | not provided | clinical testing | PubMed (21) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | 108544 | not provided | not provided | 20 | not provided | not provided | not provided | |
Last Updated: Nov 10, 2024