NM_020975.6(RET):c.2410G>A (p.Val804Met) AND Familial medullary thyroid carcinoma

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 31, 2024
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:: RCV001804750.15

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

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:

Condition(s)

Name:: Familial medullary thyroid carcinoma (MTC)
Synonyms:: Thyroid cancer, familial medullary; MTC, familial
Identifiers:: MONDO: MONDO:0007958; MedGen: C1833921; Orphanet: 653; OMIM: 155240

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002053758	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002581664	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003927229	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 3, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 18062802, 20039896, 21810974, 24336963, 24617864, 25810047, 29590403, 8797874, 25741868
SCV004239131	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	4	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Familial prevalence and age of RET germline mutations: implications for screening.

Machens A, Dralle H.

Clin Endocrinol (Oxf). 2008 Jul;69(1):81-7. Epub 2008 Jul 1.

PubMed [citation]

PMID:: 18062802

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, Verrienti A, Magendra Rao D, Sponziello M, Fabbro D, Muthu M, Durante C, Maranghi M, Damante G, Pizzolitto S, Costante G, Russo D, Santoro M, Filetti S.

Clin Endocrinol (Oxf). 2010 Oct;73(4):529-34. doi: 10.1111/j.1365-2265.2009.03757.x.

PubMed [citation]

PMID:: 20039896

See all PubMed Citations (9)

Details of each submission

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV002053758.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002581664.1

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

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

From Johns Hopkins Genomics, Johns Hopkins University, SCV003927229.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	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 KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV004239131.1

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

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). 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).

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

Last Updated: Nov 3, 2024

ClinVar

Relating variation to medicine