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NM_020975.6(RET):c.1900T>G (p.Cys634Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 3, 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:
RCV001013616.4

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:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001174224Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Pathogenic
(Mar 3, 2023) 		germlineclinical testing

PubMed (16)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Germ-line mutations in nonsyndromic pheochromocytoma.

Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, et al.

N Engl J Med. 2002 May 9;346(19):1459-66.

PubMed [citation]
PMID:
12000816

Clinical characteristics and genetic screening of an extended family with MEN2A.

Algün E, Abaci N, Kösem M, Kotan C, Köseoğlu B, Boztepe H, Sekeroğlu R, Aslan H, Topal C, Ayakta H, Uygan I, Alagöl F, Erginel-Unaltuna N, Aksoy H.

J Endocrinol Invest. 2002 Jul-Aug;25(7):603-8.

PubMed [citation]
PMID:
12150334
See all PubMed Citations (16)

Details of each submission

From Ambry Genetics, SCV001174224.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (16)

Description

The p.C634G pathogenic mutation (also known as c.1900T>G), located in coding exon 11 of the RET gene, results from a T to G substitution at nucleotide position 1900. The cysteine at codon 634 is replaced by glycine, an amino acid with highly dissimilar properties. Amino acid position 634 is a well described mutation hot spot associated with Multiple Endocrine Neoplasia Type 2A (MEN2A) and Familial Medullary Thyroid Carcinoma (FMTC). This mutation has been reported in multiple MEN2A/FMTC families (Mulligan LM et al. Nature. 1993 Jun;363:458-60; Mulligan LM et al. Nat. Genet. 1994 Jan;6:70-4; McMahon R et al. Hum. Mol. Genet. 1994 Apr;3:643-6; Marsh DJ et al. Genomics. 1994 Sep;23:477-9; Mulligan LM et al. J. Intern. Med. 1995 Oct;238:343-6; Eng C et al. JAMA. 1996 Nov;276:1575-9). It has also been reported in individuals with MEN2A and Cutaneous Lichen Amyloidosis (Seri M et al. Clin. Genet. 1997 Feb;51:86-90; Scapineli JO et al. Fam. Cancer. 2016 10;15:625-33). Additionally, this mutation has been identified in multiple individuals with a history of pheochromocytoma (Seri M et al. Clin. Genet. 1997 Feb;51:86-90; Neumann HP et al. N. Engl. J. Med. 2002 May;346:1459-66; Algün E et al. J. Endocrinol. Invest. 2002 Jul-Aug;25:603-8; Amar L et al. J. Clin. Oncol. 2005 Dec;23:8812-8). The American Thyroid Association categorizes this mutation as high risk (ATA-H) and recommends surveillance, screening, and/or possible surgical interventions in early childhood (American Thyroid Association Guidelines Task Force. Thyroid. 2009 Jun;19:565-612; Wells SA et al. Thyroid. 2015 Jun;25:567-610). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 20, 2024