NM_020975.6(RET):c.2410G>T (p.Val804Leu) AND Multiple endocrine neoplasia, type 2

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 6, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000021854.21

Allele description

NM_020975.6(RET):c.2410G>T (p.Val804Leu)

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>T (p.Val804Leu)

HGVS:

NC_000010.11:g.43119548G>T
NG_007489.1:g.47480G>T
NM_000323.2:c.2410G>T
NM_001355216.2:c.1648G>T
NM_001406743.1:c.2410G>T
NM_001406744.1:c.2410G>T
NM_001406759.1:c.2410G>T
NM_001406760.1:c.2410G>T
NM_001406761.1:c.2281G>T
NM_001406762.1:c.2281G>T
NM_001406763.1:c.2275G>T
NM_001406764.1:c.2281G>T
NM_001406765.1:c.2275G>T
NM_001406766.1:c.2122G>T
NM_001406767.1:c.2122G>T
NM_001406768.1:c.2146G>T
NM_001406769.1:c.2014G>T
NM_001406770.1:c.2122G>T
NM_001406771.1:c.1972G>T
NM_001406772.1:c.2014G>T
NM_001406773.1:c.1972G>T
NM_001406774.1:c.1885G>T
NM_001406775.1:c.1684G>T
NM_001406776.1:c.1684G>T
NM_001406777.1:c.1684G>T
NM_001406778.1:c.1684G>T
NM_001406779.1:c.1513G>T
NM_001406780.1:c.1513G>T
NM_001406781.1:c.1513G>T
NM_001406782.1:c.1513G>T
NM_001406783.1:c.1384G>T
NM_001406784.1:c.1420G>T
NM_001406785.1:c.1393G>T
NM_001406786.1:c.1384G>T
NM_001406787.1:c.1378G>T
NM_001406788.1:c.1225G>T
NM_001406789.1:c.1225G>T
NM_001406790.1:c.1225G>T
NM_001406791.1:c.1105G>T
NM_001406792.1:c.961G>T
NM_001406793.1:c.961G>T
NM_001406794.1:c.961G>T
NM_020629.2:c.2410G>T
NM_020630.7:c.2410G>T
NM_020975.6:c.2410G>TMANE SELECT
NP_000314.1:p.Val804Leu
NP_001342145.1:p.Val550Leu
NP_001342145.1:p.Val550Leu
NP_001393672.1:p.Val804Leu
NP_001393673.1:p.Val804Leu
NP_001393688.1:p.Val804Leu
NP_001393689.1:p.Val804Leu
NP_001393690.1:p.Val761Leu
NP_001393691.1:p.Val761Leu
NP_001393692.1:p.Val759Leu
NP_001393693.1:p.Val761Leu
NP_001393694.1:p.Val759Leu
NP_001393695.1:p.Val708Leu
NP_001393696.1:p.Val708Leu
NP_001393697.1:p.Val716Leu
NP_001393698.1:p.Val672Leu
NP_001393699.1:p.Val708Leu
NP_001393700.1:p.Val658Leu
NP_001393701.1:p.Val672Leu
NP_001393702.1:p.Val658Leu
NP_001393703.1:p.Val629Leu
NP_001393704.1:p.Val562Leu
NP_001393705.1:p.Val562Leu
NP_001393706.1:p.Val562Leu
NP_001393707.1:p.Val562Leu
NP_001393708.1:p.Val505Leu
NP_001393709.1:p.Val505Leu
NP_001393710.1:p.Val505Leu
NP_001393711.1:p.Val505Leu
NP_001393712.1:p.Val462Leu
NP_001393713.1:p.Val474Leu
NP_001393714.1:p.Val465Leu
NP_001393715.1:p.Val462Leu
NP_001393716.1:p.Val460Leu
NP_001393717.1:p.Val409Leu
NP_001393718.1:p.Val409Leu
NP_001393719.1:p.Val409Leu
NP_001393720.1:p.Val369Leu
NP_001393721.1:p.Val321Leu
NP_001393722.1:p.Val321Leu
NP_001393723.1:p.Val321Leu
NP_065680.1:p.Val804Leu
NP_065681.1:p.Val804Leu
NP_065681.1:p.Val804Leu
NP_065681.1:p.Val804Leu
NP_066124.1:p.Val804Leu
NP_066124.1:p.Val804Leu
LRG_518t1:c.2410G>T
LRG_518t2:c.2410G>T
LRG_518:g.47480G>T
LRG_518p1:p.Val804Leu
LRG_518p2:p.Val804Leu
NC_000010.10:g.43614996G>T
NM_001355216.1:c.1648G>T
NM_020630.4:c.2410G>T
NM_020630.6:c.2410G>T
NM_020975.4:c.2410G>T
P07949:p.Val804Leu

Protein change:

V321L; VAL804LEU

Links:

UniProtKB: P07949#VAR_006336; OMIM: 164761.0044; dbSNP: rs79658334

NCBI 1000 Genomes Browser:

rs79658334

Molecular consequence:

NM_000323.2:c.2410G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.1648G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.2410G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.2410G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.2410G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.2410G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.2281G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.2281G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.2275G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.2281G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.2275G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.2122G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.2122G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.2146G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.2014G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.2122G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.1972G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.2014G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.1972G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.1885G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.1684G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.1684G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.1684G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.1684G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.1513G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.1513G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.1513G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.1513G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.1384G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.1420G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.1393G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.1384G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406787.1:c.1378G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406788.1:c.1225G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406789.1:c.1225G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406790.1:c.1225G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406791.1:c.1105G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406792.1:c.961G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406793.1:c.961G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406794.1:c.961G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.2410G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.2410G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.2410G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Multiple endocrine neoplasia, type 2 (MEN2)
Identifiers:: MONDO: MONDO:0019003; MedGen: C4048306

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000824152	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 6, 2023)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 7784092, 10235148, 15741265, 16343097, 18058472, 18062802, 19469690, 21626080, 25810047, 26269449, 9242375, 16507829, 26046350, 8797874, 9452077, 10876191, 28492532
SCV004357248	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 18, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 7784092, 9242375, 10235148, 10445857, 11932300, 12694233, 15741265, 20516206, 21626080, 25810047, 26046350, 25741868
SCV004838669	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 13, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 7784092, 9242375, 10445857, 11932300, 12694233, 15741265, 16343097, 18058472, 18062802, 19469690, 21626080, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000824152

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 6, 2023)

germline

clinical testing

PubMed (17)
[See all records that cite these PMIDs]

SCV004357248

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 18, 2023)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV004838669

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 13, 2023)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients.

Currás-Freixes M, Inglada-Pérez L, Mancikova V, Montero-Conde C, Letón R, Comino-Méndez I, Apellániz-Ruiz M, Sánchez-Barroso L, Aguirre Sánchez-Covisa M, Alcázar V, Aller J, Álvarez-Escolá C, Andía-Melero VM, Azriel-Mira S, Calatayud-Gutiérrez M, Díaz JÁ, Díez-Hernández A, Lamas-Oliveira C, Marazuela M, Matias-Guiu X, Meoro-Avilés A, Patiño-García A, et al.

J Med Genet. 2015 Oct;52(10):647-56. doi: 10.1136/jmedgenet-2015-103218. Epub 2015 Aug 12.

PubMed [citation]

PMID:: 26269449

BAY 43-9006 inhibition of oncogenic RET mutants.

Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, Santoro M.

J Natl Cancer Inst. 2006 Mar 1;98(5):326-34.

PubMed [citation]

PMID:: 16507829

See all PubMed Citations (22)

Details of each submission

From Invitae, SCV000824152.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

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.

#	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 Color Diagnostics, LLC DBA Color Health, SCV004357248.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

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.

#	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, SCV004838669.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (12)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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