NM_020975.6(RET):c.2753T>C (p.Met918Thr) AND Multiple endocrine neoplasia type 2A

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 15, 2020
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:: RCV000175096.16

Allele description [Variation Report for NM_020975.6(RET):c.2753T>C (p.Met918Thr)]

NM_020975.6(RET):c.2753T>C (p.Met918Thr)

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.2753T>C (p.Met918Thr)

Other names:

p.M918T:ATG>ACG

HGVS:

NC_000010.11:g.43121968T>C
NG_007489.1:g.49900T>C
NM_000323.2:c.2753T>C
NM_001355216.2:c.1991T>C
NM_001406743.1:c.2753T>C
NM_001406744.1:c.2753T>C
NM_001406759.1:c.2753T>C
NM_001406760.1:c.2753T>C
NM_001406761.1:c.2624T>C
NM_001406762.1:c.2624T>C
NM_001406763.1:c.2618T>C
NM_001406764.1:c.2624T>C
NM_001406765.1:c.2618T>C
NM_001406766.1:c.2465T>C
NM_001406767.1:c.2465T>C
NM_001406768.1:c.2489T>C
NM_001406769.1:c.2357T>C
NM_001406770.1:c.2465T>C
NM_001406771.1:c.2315T>C
NM_001406772.1:c.2357T>C
NM_001406773.1:c.2315T>C
NM_001406774.1:c.2228T>C
NM_001406775.1:c.2027T>C
NM_001406776.1:c.2027T>C
NM_001406777.1:c.2027T>C
NM_001406778.1:c.2027T>C
NM_001406779.1:c.1856T>C
NM_001406780.1:c.1856T>C
NM_001406781.1:c.1856T>C
NM_001406782.1:c.1856T>C
NM_001406783.1:c.1727T>C
NM_001406784.1:c.1763T>C
NM_001406785.1:c.1736T>C
NM_001406786.1:c.1727T>C
NM_001406787.1:c.1721T>C
NM_001406788.1:c.1568T>C
NM_001406789.1:c.1568T>C
NM_001406790.1:c.1568T>C
NM_001406791.1:c.1448T>C
NM_001406792.1:c.1304T>C
NM_001406793.1:c.1304T>C
NM_001406794.1:c.1304T>C
NM_020629.2:c.2753T>C
NM_020630.7:c.2753T>C
NM_020975.6:c.2753T>CMANE SELECT
NP_000314.1:p.Met918Thr
NP_001342145.1:p.Met664Thr
NP_001342145.1:p.Met664Thr
NP_001393672.1:p.Met918Thr
NP_001393673.1:p.Met918Thr
NP_001393688.1:p.Met918Thr
NP_001393689.1:p.Met918Thr
NP_001393690.1:p.Met875Thr
NP_001393691.1:p.Met875Thr
NP_001393692.1:p.Met873Thr
NP_001393693.1:p.Met875Thr
NP_001393694.1:p.Met873Thr
NP_001393695.1:p.Met822Thr
NP_001393696.1:p.Met822Thr
NP_001393697.1:p.Met830Thr
NP_001393698.1:p.Met786Thr
NP_001393699.1:p.Met822Thr
NP_001393700.1:p.Met772Thr
NP_001393701.1:p.Met786Thr
NP_001393702.1:p.Met772Thr
NP_001393703.1:p.Met743Thr
NP_001393704.1:p.Met676Thr
NP_001393705.1:p.Met676Thr
NP_001393706.1:p.Met676Thr
NP_001393707.1:p.Met676Thr
NP_001393708.1:p.Met619Thr
NP_001393709.1:p.Met619Thr
NP_001393710.1:p.Met619Thr
NP_001393711.1:p.Met619Thr
NP_001393712.1:p.Met576Thr
NP_001393713.1:p.Met588Thr
NP_001393714.1:p.Met579Thr
NP_001393715.1:p.Met576Thr
NP_001393716.1:p.Met574Thr
NP_001393717.1:p.Met523Thr
NP_001393718.1:p.Met523Thr
NP_001393719.1:p.Met523Thr
NP_001393720.1:p.Met483Thr
NP_001393721.1:p.Met435Thr
NP_001393722.1:p.Met435Thr
NP_001393723.1:p.Met435Thr
NP_065680.1:p.Met918Thr
NP_065681.1:p.Met918Thr
NP_065681.1:p.Met918Thr
NP_065681.1:p.Met918Thr
NP_066124.1:p.Met918Thr
NP_066124.1:p.Met918Thr
NP_066124.1:p.Met918Thr
LRG_518t1:c.2753T>C
LRG_518t2:c.2753T>C
LRG_518:g.49900T>C
LRG_518p1:p.Met918Thr
LRG_518p2:p.Met918Thr
NC_000010.10:g.43617416T>C
NM_001355216.1:c.1991T>C
NM_020630.4:c.2753T>C
NM_020630.6:c.2753T>C
NM_020630.7:c.2753T>C
NM_020975.4:c.2753T>C
NM_020975.5:c.2753T>C
P07949:p.Met918Thr

Protein change:

M435T; MET918THR

Links:

UniProtKB: P07949#VAR_006342; OMIM: 164761.0013; dbSNP: rs74799832

NCBI 1000 Genomes Browser:

rs74799832

Molecular consequence:

NM_000323.2:c.2753T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.1991T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.2753T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.2753T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.2753T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.2753T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.2624T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.2624T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.2618T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.2624T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.2618T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.2465T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.2465T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.2489T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.2357T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.2465T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.2315T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.2357T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.2315T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.2228T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.2027T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.2027T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.2027T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.2027T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.1856T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.1856T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.1856T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.1856T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.1727T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.1763T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.1736T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.1727T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406787.1:c.1721T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406788.1:c.1568T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406789.1:c.1568T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406790.1:c.1568T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406791.1:c.1448T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406792.1:c.1304T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406793.1:c.1304T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406794.1:c.1304T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.2753T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.2753T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.2753T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Multiple endocrine neoplasia type 2A
Synonyms:: MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA; Sipple syndrome; MEN 2A; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008234; MeSH: D018813; MedGen: C0025268; Orphanet: 653; OMIM: 171400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000510481	Database of Curated Mutations (DoCM)	no assertion criteria provided	Likely pathogenic (May 13, 2016)	somatic	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000677723	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Pathogenic (Oct 21, 2016)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10679286, 21810974, 8918855, 9242375 Citation Link,
SCV000782260	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001478177	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 15, 2020)	germline	research	PubMed (2) [See all records that cite these PMIDs] 28873162, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	somatic	yes	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

RET activation by germline MEN2A and MEN2B mutations.

Borrello MG, Smith DP, Pasini B, Bongarzone I, Greco A, Lorenzo MJ, Arighi E, Miranda C, Eng C, Alberti L, et al.

Oncogene. 1995 Dec 7;11(11):2419-27.

PubMed [citation]

PMID:: 8570194

A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations.

Iwashita T, Murakami H, Kurokawa K, Kawai K, Miyauchi A, Futami H, Qiao S, Ichihara M, Takahashi M.

Biochem Biophys Res Commun. 2000 Feb 24;268(3):804-8.

PubMed [citation]

PMID:: 10679286

See all PubMed Citations (7)

Details of each submission

From Database of Curated Mutations (DoCM), SCV000510481.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

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

From Counsyl, SCV000677723.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

M918T is associated only with MEN2B phenotype.

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

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000782260.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pediatrics, Memorial Sloan Kettering Cancer Center, SCV001478177.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 12, 2024

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