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NM_020975.6(RET):c.1901G>A (p.Cys634Tyr) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 6, 2022
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:
RCV000129490.14

Allele description [Variation Report for NM_020975.6(RET):c.1901G>A (p.Cys634Tyr)]

NM_020975.6(RET):c.1901G>A (p.Cys634Tyr)

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.1901G>A (p.Cys634Tyr)
Other names:
p.C634Y:TGC>TAC
HGVS:
  • NC_000010.11:g.43114501G>A
  • NG_007489.1:g.42433G>A
  • NM_000323.2:c.1901G>A
  • NM_001355216.2:c.1139G>A
  • NM_001406743.1:c.1901G>A
  • NM_001406744.1:c.1901G>A
  • NM_001406759.1:c.1901G>A
  • NM_001406760.1:c.1901G>A
  • NM_001406761.1:c.1772G>A
  • NM_001406762.1:c.1772G>A
  • NM_001406764.1:c.1772G>A
  • NM_001406766.1:c.1613G>A
  • NM_001406767.1:c.1613G>A
  • NM_001406769.1:c.1505G>A
  • NM_001406770.1:c.1613G>A
  • NM_001406771.1:c.1463G>A
  • NM_001406772.1:c.1505G>A
  • NM_001406773.1:c.1463G>A
  • NM_001406774.1:c.1376G>A
  • NM_001406775.1:c.1175G>A
  • NM_001406776.1:c.1175G>A
  • NM_001406777.1:c.1175G>A
  • NM_001406778.1:c.1175G>A
  • NM_001406779.1:c.1004G>A
  • NM_001406780.1:c.1004G>A
  • NM_001406781.1:c.1004G>A
  • NM_001406782.1:c.1004G>A
  • NM_001406783.1:c.875G>A
  • NM_001406784.1:c.911G>A
  • NM_001406785.1:c.884G>A
  • NM_001406786.1:c.875G>A
  • NM_001406788.1:c.716G>A
  • NM_001406789.1:c.716G>A
  • NM_001406790.1:c.716G>A
  • NM_001406791.1:c.596G>A
  • NM_001406792.1:c.452G>A
  • NM_001406793.1:c.452G>A
  • NM_001406794.1:c.452G>A
  • NM_020629.2:c.1901G>A
  • NM_020630.7:c.1901G>A
  • NM_020975.6:c.1901G>AMANE SELECT
  • NP_000314.1:p.Cys634Tyr
  • NP_001342145.1:p.Cys380Tyr
  • NP_001342145.1:p.Cys380Tyr
  • NP_001393672.1:p.Cys634Tyr
  • NP_001393673.1:p.Cys634Tyr
  • NP_001393688.1:p.Cys634Tyr
  • NP_001393689.1:p.Cys634Tyr
  • NP_001393690.1:p.Cys591Tyr
  • NP_001393691.1:p.Cys591Tyr
  • NP_001393693.1:p.Cys591Tyr
  • NP_001393695.1:p.Cys538Tyr
  • NP_001393696.1:p.Cys538Tyr
  • NP_001393698.1:p.Cys502Tyr
  • NP_001393699.1:p.Cys538Tyr
  • NP_001393700.1:p.Cys488Tyr
  • NP_001393701.1:p.Cys502Tyr
  • NP_001393702.1:p.Cys488Tyr
  • NP_001393703.1:p.Cys459Tyr
  • NP_001393704.1:p.Cys392Tyr
  • NP_001393705.1:p.Cys392Tyr
  • NP_001393706.1:p.Cys392Tyr
  • NP_001393707.1:p.Cys392Tyr
  • NP_001393708.1:p.Cys335Tyr
  • NP_001393709.1:p.Cys335Tyr
  • NP_001393710.1:p.Cys335Tyr
  • NP_001393711.1:p.Cys335Tyr
  • NP_001393712.1:p.Cys292Tyr
  • NP_001393713.1:p.Cys304Tyr
  • NP_001393714.1:p.Cys295Tyr
  • NP_001393715.1:p.Cys292Tyr
  • NP_001393717.1:p.Cys239Tyr
  • NP_001393718.1:p.Cys239Tyr
  • NP_001393719.1:p.Cys239Tyr
  • NP_001393720.1:p.Cys199Tyr
  • NP_001393721.1:p.Cys151Tyr
  • NP_001393722.1:p.Cys151Tyr
  • NP_001393723.1:p.Cys151Tyr
  • NP_065680.1:p.Cys634Tyr
  • NP_065681.1:p.Cys634Tyr
  • NP_065681.1:p.Cys634Tyr
  • NP_065681.1:p.Cys634Tyr
  • NP_066124.1:p.Cys634Tyr
  • NP_066124.1:p.Cys634Tyr
  • LRG_518t1:c.1901G>A
  • LRG_518t2:c.1901G>A
  • LRG_518:g.42433G>A
  • LRG_518p1:p.Cys634Tyr
  • LRG_518p2:p.Cys634Tyr
  • NC_000010.10:g.43609949G>A
  • NM_001355216.1:c.1139G>A
  • NM_020630.4:c.1901G>A
  • NM_020630.6:c.1901G>A
  • NM_020975.4:c.1901G>A
  • P07949:p.Cys634Tyr
Protein change:
C151Y; CYS634TYR
Links:
UniProtKB: P07949#VAR_006325; OMIM: 164761.0004; dbSNP: rs75996173
NCBI 1000 Genomes Browser:
rs75996173
Molecular consequence:
  • NM_000323.2:c.1901G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001355216.2:c.1139G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406743.1:c.1901G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406744.1:c.1901G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406759.1:c.1901G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406760.1:c.1901G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406761.1:c.1772G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406762.1:c.1772G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406764.1:c.1772G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406766.1:c.1613G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406767.1:c.1613G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406769.1:c.1505G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406770.1:c.1613G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406771.1:c.1463G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406772.1:c.1505G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406773.1:c.1463G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406774.1:c.1376G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406775.1:c.1175G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406776.1:c.1175G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406777.1:c.1175G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406778.1:c.1175G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406779.1:c.1004G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406780.1:c.1004G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406781.1:c.1004G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406782.1:c.1004G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406783.1:c.875G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406784.1:c.911G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406785.1:c.884G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406786.1:c.875G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406788.1:c.716G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406789.1:c.716G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406790.1:c.716G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406791.1:c.596G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406792.1:c.452G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406793.1:c.452G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406794.1:c.452G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020629.2:c.1901G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020630.7:c.1901G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020975.6:c.1901G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV000184262Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Pathogenic
(Jun 6, 2022) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not 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

Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship.

Yip L, Cote GJ, Shapiro SE, Ayers GD, Herzog CE, Sellin RV, Sherman SI, Gagel RF, Lee JE, Evans DB.

Arch Surg. 2003 Apr;138(4):409-16; discussion 416.

PubMed [citation]
PMID:
12686527
See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000184262.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (8)

Description

The p.C634Y pathogenic mutation (also known as c.1901G>A) is located in coding exon 11 of the RET gene. This alteration results from a G to A substitution at nucleotide position 1901. The cysteine at codon 634 is replaced by tyrosine, an amino acid with highly dissimilar properties. The p.C634Y mutation has been reported in several unrelated families diagnosed with MEN2A and/or familial medullary thyroid carcinoma (FMTC) (Mulligan et al. Nature. 1993;363:458-460; Marsh DJ et al. Genomics. 1994;23(2):477-479; Hedayati et al. J Thyroid Res. 2011;2011:264248; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122). Amino acid position 634 is a well described mutation hot spot associated with MEN2A/FMTC. Studies evaluating genotype-phenotype correlation suggest higher penetrance for pheochromocytoma in MEN2 patients with mutations at amino acid position 634 (Neumann HP et al. N. Engl. J. Med. 2002;346:1459-66, Quayle FJ et al. Surgery 2007;142:800-5; Yip L et al. Arch Surg 2003;138:409-16). Revised American Thyroid Association Guidelines categorize the p.C634Y alteration as high risk (ATA-H) and recommend surveillance and prophylactic surgery in early childhood (Wells SA et al. Thyroid 2015 Jun;25(6):567-610). Of note, this alteration has been referred to as p.C380Y (c.1832G>A) and p.C634Y (c.2096G>A) in the published literature. Based on the available evidence, p.C634Y is classified as a pathogenic mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Apr 15, 2024