NM_020975.6(RET):c.1900T>G (p.Cys634Gly) AND Multiple endocrine neoplasia, type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 5, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000654584.9

Allele description [Variation Report for NM_020975.6(RET):c.1900T>G (p.Cys634Gly)]

NM_020975.6(RET):c.1900T>G (p.Cys634Gly)

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.1900T>G (p.Cys634Gly)

Other names:

p.C634G:TGC>GGC

HGVS:

NC_000010.11:g.43114500T>G
NG_007489.1:g.42432T>G
NM_000323.2:c.1900T>G
NM_001355216.2:c.1138T>G
NM_001406743.1:c.1900T>G
NM_001406744.1:c.1900T>G
NM_001406759.1:c.1900T>G
NM_001406760.1:c.1900T>G
NM_001406761.1:c.1771T>G
NM_001406762.1:c.1771T>G
NM_001406764.1:c.1771T>G
NM_001406766.1:c.1612T>G
NM_001406767.1:c.1612T>G
NM_001406769.1:c.1504T>G
NM_001406770.1:c.1612T>G
NM_001406771.1:c.1462T>G
NM_001406772.1:c.1504T>G
NM_001406773.1:c.1462T>G
NM_001406774.1:c.1375T>G
NM_001406775.1:c.1174T>G
NM_001406776.1:c.1174T>G
NM_001406777.1:c.1174T>G
NM_001406778.1:c.1174T>G
NM_001406779.1:c.1003T>G
NM_001406780.1:c.1003T>G
NM_001406781.1:c.1003T>G
NM_001406782.1:c.1003T>G
NM_001406783.1:c.874T>G
NM_001406784.1:c.910T>G
NM_001406785.1:c.883T>G
NM_001406786.1:c.874T>G
NM_001406788.1:c.715T>G
NM_001406789.1:c.715T>G
NM_001406790.1:c.715T>G
NM_001406791.1:c.595T>G
NM_001406792.1:c.451T>G
NM_001406793.1:c.451T>G
NM_001406794.1:c.451T>G
NM_020629.2:c.1900T>G
NM_020630.7:c.1900T>G
NM_020975.6:c.1900T>GMANE SELECT
NP_000314.1:p.Cys634Gly
NP_001342145.1:p.Cys380Gly
NP_001342145.1:p.Cys380Gly
NP_001393672.1:p.Cys634Gly
NP_001393673.1:p.Cys634Gly
NP_001393688.1:p.Cys634Gly
NP_001393689.1:p.Cys634Gly
NP_001393690.1:p.Cys591Gly
NP_001393691.1:p.Cys591Gly
NP_001393693.1:p.Cys591Gly
NP_001393695.1:p.Cys538Gly
NP_001393696.1:p.Cys538Gly
NP_001393698.1:p.Cys502Gly
NP_001393699.1:p.Cys538Gly
NP_001393700.1:p.Cys488Gly
NP_001393701.1:p.Cys502Gly
NP_001393702.1:p.Cys488Gly
NP_001393703.1:p.Cys459Gly
NP_001393704.1:p.Cys392Gly
NP_001393705.1:p.Cys392Gly
NP_001393706.1:p.Cys392Gly
NP_001393707.1:p.Cys392Gly
NP_001393708.1:p.Cys335Gly
NP_001393709.1:p.Cys335Gly
NP_001393710.1:p.Cys335Gly
NP_001393711.1:p.Cys335Gly
NP_001393712.1:p.Cys292Gly
NP_001393713.1:p.Cys304Gly
NP_001393714.1:p.Cys295Gly
NP_001393715.1:p.Cys292Gly
NP_001393717.1:p.Cys239Gly
NP_001393718.1:p.Cys239Gly
NP_001393719.1:p.Cys239Gly
NP_001393720.1:p.Cys199Gly
NP_001393721.1:p.Cys151Gly
NP_001393722.1:p.Cys151Gly
NP_001393723.1:p.Cys151Gly
NP_065680.1:p.Cys634Gly
NP_065681.1:p.Cys634Gly
NP_065681.1:p.Cys634Gly
NP_065681.1:p.Cys634Gly
NP_066124.1:p.Cys634Gly
NP_066124.1:p.Cys634Gly
LRG_518t1:c.1900T>G
LRG_518t2:c.1900T>G
LRG_518:g.42432T>G
LRG_518p1:p.Cys634Gly
LRG_518p2:p.Cys634Gly
NC_000010.10:g.43609948T>G
NM_001355216.1:c.1138T>G
NM_020630.4:c.1900T>G
NM_020630.6:c.1900T>G
NM_020975.4:c.1900T>G
P07949:p.Cys634Gly

Protein change:

C151G; CYS634GLY

Links:

UniProtKB: P07949#VAR_006323; OMIM: 164761.0003; dbSNP: rs75076352

NCBI 1000 Genomes Browser:

rs75076352

Molecular consequence:

NM_000323.2:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.1138T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.1771T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.1771T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.1771T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.1612T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.1612T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.1504T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.1612T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.1462T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.1504T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.1462T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.1375T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.1174T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.1174T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.1174T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.1174T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.1003T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.1003T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.1003T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.1003T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.874T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.910T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.883T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.874T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406788.1:c.715T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406789.1:c.715T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406790.1:c.715T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406791.1:c.595T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406792.1:c.451T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406793.1:c.451T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406794.1:c.451T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.1900T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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PREDICTED: Mus musculus N-terminal EF-hand calcium binding protein 3 (Necab3), t...
PREDICTED: Mus musculus N-terminal EF-hand calcium binding protein 3 (Necab3), transcript variant X8, mRNA
gi|1907142097|ref|XM_030251902.2|

Nucleotide
Homo sapiens carnitine palmitoyltransferase 2 (CPT2), transcript variant 1, mRNA
Homo sapiens carnitine palmitoyltransferase 2 (CPT2), transcript variant 1, mRNA
gi|169790951|ref|NM_000098.2|

Nucleotide
LOC132409794 [Mus musculus]
LOC132409794 [Mus musculus]
Gene ID:132409794

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000776478	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 5, 2023)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 9111993, 9950371, 12150334, 19201392, 26230854, 26356818, 7824936, 8099202, 8103403, 8918855, 11939755, 12000816, 16865647, 21765987, 21810974, 24331334, 24716929, 26678667, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000776478

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 5, 2023)

germline

clinical testing

PubMed (19)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Cys634Gly substitution of the RET proto-oncogene in a family with recurrence of multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis.

Seri M, Celli I, Betsos N, Claudiani F, Camera G, Romeo G.

Clin Genet. 1997 Feb;51(2):86-90.

PubMed [citation]

PMID:: 9111993

High prevalence of the C634Y mutation in the RET proto-oncogene in MEN 2A families in Spain.

Sánchez B, Robledo M, Biarnes J, Sáez ME, Volpini V, Benítez J, Navarro E, Ruiz A, Antiñolo G, Borrego S.

J Med Genet. 1999 Jan;36(1):68-70.

PubMed [citation]

PMID:: 9950371
PMCID:: PMC1762956

See all PubMed Citations (19)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000776478.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (19)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 634 of the RET protein (p.Cys634Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with medullary thyroid carcinoma or pheochromcytomas and multiple endocrine neoplasia type 2 (PMID: 8099202, 9111993, 9950371, 12000816, 12150334, 19201392, 21765987, 26230854, 26356818). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13908). 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. This variant disrupts the p.Cys634 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7824936, 8099202, 8103403, 8918855, 11939755, 12000816, 16865647, 21765987, 21810974, 24331334, 24716929, 26678667). 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

Last Updated: Sep 29, 2024

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