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NM_020975.6(RET):c.1423C>T (p.Arg475Trp) AND Hereditary cancer-predisposing syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 27, 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:
RCV001011519.4

Allele description

NM_020975.6(RET):c.1423C>T (p.Arg475Trp)

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.1423C>T (p.Arg475Trp)
HGVS:
  • NC_000010.11:g.43111366C>T
  • NG_007489.1:g.39298C>T
  • NM_000323.2:c.1423C>T
  • NM_001355216.2:c.661C>T
  • NM_001406743.1:c.1423C>T
  • NM_001406744.1:c.1423C>T
  • NM_001406759.1:c.1423C>T
  • NM_001406760.1:c.1423C>T
  • NM_001406761.1:c.1294C>T
  • NM_001406762.1:c.1294C>T
  • NM_001406763.1:c.1423C>T
  • NM_001406764.1:c.1294C>T
  • NM_001406765.1:c.1423C>T
  • NM_001406766.1:c.1135C>T
  • NM_001406767.1:c.1135C>T
  • NM_001406768.1:c.1294C>T
  • NM_001406769.1:c.1027C>T
  • NM_001406770.1:c.1135C>T
  • NM_001406771.1:c.985C>T
  • NM_001406772.1:c.1027C>T
  • NM_001406773.1:c.985C>T
  • NM_001406774.1:c.898C>T
  • NM_001406775.1:c.697C>T
  • NM_001406776.1:c.697C>T
  • NM_001406777.1:c.697C>T
  • NM_001406778.1:c.697C>T
  • NM_001406784.1:c.433C>T
  • NM_020629.2:c.1423C>T
  • NM_020630.7:c.1423C>T
  • NM_020975.6:c.1423C>TMANE SELECT
  • NP_000314.1:p.Arg475Trp
  • NP_001342145.1:p.Arg221Trp
  • NP_001342145.1:p.Arg221Trp
  • NP_001393672.1:p.Arg475Trp
  • NP_001393673.1:p.Arg475Trp
  • NP_001393688.1:p.Arg475Trp
  • NP_001393689.1:p.Arg475Trp
  • NP_001393690.1:p.Arg432Trp
  • NP_001393691.1:p.Arg432Trp
  • NP_001393692.1:p.Arg475Trp
  • NP_001393693.1:p.Arg432Trp
  • NP_001393694.1:p.Arg475Trp
  • NP_001393695.1:p.Arg379Trp
  • NP_001393696.1:p.Arg379Trp
  • NP_001393697.1:p.Arg432Trp
  • NP_001393698.1:p.Arg343Trp
  • NP_001393699.1:p.Arg379Trp
  • NP_001393700.1:p.Arg329Trp
  • NP_001393701.1:p.Arg343Trp
  • NP_001393702.1:p.Arg329Trp
  • NP_001393703.1:p.Arg300Trp
  • NP_001393704.1:p.Arg233Trp
  • NP_001393705.1:p.Arg233Trp
  • NP_001393706.1:p.Arg233Trp
  • NP_001393707.1:p.Arg233Trp
  • NP_001393713.1:p.Arg145Trp
  • NP_065680.1:p.Arg475Trp
  • NP_065681.1:p.Arg475Trp
  • NP_065681.1:p.Arg475Trp
  • NP_065681.1:p.Arg475Trp
  • NP_066124.1:p.Arg475Trp
  • NP_066124.1:p.Arg475Trp
  • LRG_518t1:c.1423C>T
  • LRG_518t2:c.1423C>T
  • LRG_518:g.39298C>T
  • LRG_518p1:p.Arg475Trp
  • LRG_518p2:p.Arg475Trp
  • NC_000010.10:g.43606814C>T
  • NM_001355216.1:c.661C>T
  • NM_020630.4:c.1423C>T
  • NM_020630.6:c.1423C>T
  • NM_020975.4:c.1423C>T
Protein change:
R145W
Links:
dbSNP: rs746512075
NCBI 1000 Genomes Browser:
rs746512075
Molecular consequence:
  • NM_000323.2:c.1423C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001355216.2:c.661C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406743.1:c.1423C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406744.1:c.1423C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406759.1:c.1423C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406760.1:c.1423C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406761.1:c.1294C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406762.1:c.1294C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406763.1:c.1423C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406764.1:c.1294C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406765.1:c.1423C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406766.1:c.1135C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406767.1:c.1135C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406768.1:c.1294C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406769.1:c.1027C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406770.1:c.1135C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406771.1:c.985C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406772.1:c.1027C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406773.1:c.985C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406774.1:c.898C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406775.1:c.697C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406776.1:c.697C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406777.1:c.697C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406778.1:c.697C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406784.1:c.433C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020629.2:c.1423C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020630.7:c.1423C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020975.6:c.1423C>T - 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
SCV001171850Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Uncertain significance
(Mar 27, 2023) 		germlineclinical testing

PubMed (2)
[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

Association between c135G/A genotype and RET proto-oncogene germline mutations and phenotype of Hirschsprung's disease.

Fitze G, Cramer J, Ziegler A, Schierz M, Schreiber M, Kuhlisch E, Roesner D, Schackert HK.

Lancet. 2002 Apr 6;359(9313):1200-5.

PubMed [citation]
PMID:
11955539

Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations.

Kjaer S, Hanrahan S, Totty N, McDonald NQ.

Nat Struct Mol Biol. 2010 Jun;17(6):726-31. doi: 10.1038/nsmb.1808. Epub 2010 May 16.

PubMed [citation]
PMID:
20473317

Details of each submission

From Ambry Genetics, SCV001171850.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The p.R475W variant (also known as c.1423C>T), located in coding exon 7 of the RET gene, results from a C to T substitution at nucleotide position 1423. The arginine at codon 475 is replaced by tryptophan, an amino acid with dissimilar properties. Structural and functional analyses indicate that this alteration results in protein misfolding (Kjaer S, et al. Hum. Mol. Genet. 2003 Sep;12(17):2133-44; Kjaer S, et al. Nat. Struct. Mol. Biol. 2010 Jun; 17(6):726-31). This alteration has been previously identified in an individual with sporadic Hirschsprung disease (Fitze G, et al. Lancet 2002 Apr; 359(9313):1200-5). It has not been reported in an individual with a diagnosis of multiple endocrine neoplasia type 2 (MEN2) to date. Based on protein sequence alignment, this amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

Last Updated: Apr 20, 2024