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NM_020975.6(RET):c.1893_1898del (p.Asp631_Leu633delinsGlu) AND MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 19, 2020
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:
RCV001267832.3

Allele description [Variation Report for NM_020975.6(RET):c.1893_1898del (p.Asp631_Leu633delinsGlu)]

NM_020975.6(RET):c.1893_1898del (p.Asp631_Leu633delinsGlu)

Gene:
RET:ret proto-oncogene [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
10q11.21
Genomic location:
Preferred name:
NM_020975.6(RET):c.1893_1898del (p.Asp631_Leu633delinsGlu)
HGVS:
  • NC_000010.11:g.43114493_43114498del
  • NG_007489.1:g.42425_42430del
  • NM_000323.2:c.1893_1898delCGAGCT
  • NM_001355216.2:c.1131_1136delCGAGCT
  • NM_001406743.1:c.1893_1898delCGAGCT
  • NM_001406744.1:c.1893_1898delCGAGCT
  • NM_001406759.1:c.1893_1898delCGAGCT
  • NM_001406760.1:c.1893_1898delCGAGCT
  • NM_001406761.1:c.1764_1769delCGAGCT
  • NM_001406762.1:c.1764_1769delCGAGCT
  • NM_001406764.1:c.1764_1769delCGAGCT
  • NM_001406766.1:c.1605_1610delCGAGCT
  • NM_001406767.1:c.1605_1610delCGAGCT
  • NM_001406769.1:c.1497_1502delCGAGCT
  • NM_001406770.1:c.1605_1610delCGAGCT
  • NM_001406771.1:c.1455_1460delCGAGCT
  • NM_001406772.1:c.1497_1502delCGAGCT
  • NM_001406773.1:c.1455_1460delCGAGCT
  • NM_001406774.1:c.1368_1373delCGAGCT
  • NM_001406775.1:c.1167_1172delCGAGCT
  • NM_001406776.1:c.1167_1172delCGAGCT
  • NM_001406777.1:c.1167_1172delCGAGCT
  • NM_001406778.1:c.1167_1172delCGAGCT
  • NM_001406779.1:c.996_1001delCGAGCT
  • NM_001406780.1:c.996_1001delCGAGCT
  • NM_001406781.1:c.996_1001delCGAGCT
  • NM_001406782.1:c.996_1001delCGAGCT
  • NM_001406783.1:c.867_872delCGAGCT
  • NM_001406784.1:c.903_908delCGAGCT
  • NM_001406785.1:c.876_881delCGAGCT
  • NM_001406786.1:c.867_872delCGAGCT
  • NM_001406788.1:c.708_713delCGAGCT
  • NM_001406789.1:c.708_713delCGAGCT
  • NM_001406790.1:c.708_713delCGAGCT
  • NM_001406791.1:c.588_593delCGAGCT
  • NM_001406792.1:c.444_449delCGAGCT
  • NM_001406793.1:c.444_449delCGAGCT
  • NM_001406794.1:c.444_449delCGAGCT
  • NM_020629.2:c.1893_1898delCGAGCT
  • NM_020630.7:c.1893_1898delCGAGCT
  • NM_020975.6:c.1893_1898delMANE SELECT
  • NP_000314.1:p.Asp631_Leu633delinsGlu
  • NP_001342145.1:p.Asp377_Leu379delinsGlu
  • NP_001342145.1:p.Asp377_Leu379delinsGlu
  • NP_001393672.1:p.Asp631_Leu633delinsGlu
  • NP_001393673.1:p.Asp631_Leu633delinsGlu
  • NP_001393688.1:p.Asp631_Leu633delinsGlu
  • NP_001393689.1:p.Asp631_Leu633delinsGlu
  • NP_001393690.1:p.Asp588_Leu590delinsGlu
  • NP_001393691.1:p.Asp588_Leu590delinsGlu
  • NP_001393693.1:p.Asp588_Leu590delinsGlu
  • NP_001393695.1:p.Asp535_Leu537delinsGlu
  • NP_001393696.1:p.Asp535_Leu537delinsGlu
  • NP_001393698.1:p.Asp499_Leu501delinsGlu
  • NP_001393699.1:p.Asp535_Leu537delinsGlu
  • NP_001393700.1:p.Asp485_Leu487delinsGlu
  • NP_001393701.1:p.Asp499_Leu501delinsGlu
  • NP_001393702.1:p.Asp485_Leu487delinsGlu
  • NP_001393703.1:p.Asp456_Leu458delinsGlu
  • NP_001393704.1:p.Asp389_Leu391delinsGlu
  • NP_001393705.1:p.Asp389_Leu391delinsGlu
  • NP_001393706.1:p.Asp389_Leu391delinsGlu
  • NP_001393707.1:p.Asp389_Leu391delinsGlu
  • NP_001393708.1:p.Asp332_Leu334delinsGlu
  • NP_001393709.1:p.Asp332_Leu334delinsGlu
  • NP_001393710.1:p.Asp332_Leu334delinsGlu
  • NP_001393711.1:p.Asp332_Leu334delinsGlu
  • NP_001393712.1:p.Asp289_Leu291delinsGlu
  • NP_001393713.1:p.Asp301_Leu303delinsGlu
  • NP_001393714.1:p.Asp292_Leu294delinsGlu
  • NP_001393715.1:p.Asp289_Leu291delinsGlu
  • NP_001393717.1:p.Asp236_Leu238delinsGlu
  • NP_001393718.1:p.Asp236_Leu238delinsGlu
  • NP_001393719.1:p.Asp236_Leu238delinsGlu
  • NP_001393720.1:p.Asp196_Leu198delinsGlu
  • NP_001393721.1:p.Asp148_Leu150delinsGlu
  • NP_001393722.1:p.Asp148_Leu150delinsGlu
  • NP_001393723.1:p.Asp148_Leu150delinsGlu
  • NP_065680.1:p.Asp631_Leu633delinsGlu
  • NP_065681.1:p.Asp631_Leu633delinsGlu
  • NP_065681.1:p.Asp631_Leu633delinsGlu
  • NP_065681.1:p.Asp631_Leu633delinsGlu
  • NP_066124.1:p.Asp631_Leu633delinsGlu
  • NP_066124.1:p.Asp631_Leu633delinsGlu
  • LRG_518t1:c.1893_1898del
  • LRG_518t2:c.1893_1898del
  • LRG_518:g.42425_42430del
  • LRG_518p1:p.Asp631_Leu633delinsGlu
  • LRG_518p2:p.Asp631_Leu633delinsGlu
  • NC_000010.10:g.43609941_43609946del
  • NM_001355216.1:c.1131_1136del
  • NM_020630.4:c.1893_1898delCGAGCT
  • NM_020630.6:c.1893_1898del
  • NM_020975.4:c.1893_1898delCGAGCT
  • NM_020975.6:c.1893_1898delCGAGCTMANE SELECT
Links:
dbSNP: rs121913307
NCBI 1000 Genomes Browser:
rs121913307
Molecular consequence:
  • NM_000323.2:c.1893_1898delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001355216.2:c.1131_1136delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406743.1:c.1893_1898delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406744.1:c.1893_1898delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406759.1:c.1893_1898delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406760.1:c.1893_1898delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406761.1:c.1764_1769delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406762.1:c.1764_1769delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406764.1:c.1764_1769delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406766.1:c.1605_1610delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406767.1:c.1605_1610delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406769.1:c.1497_1502delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406770.1:c.1605_1610delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406771.1:c.1455_1460delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406772.1:c.1497_1502delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406773.1:c.1455_1460delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406774.1:c.1368_1373delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406775.1:c.1167_1172delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406776.1:c.1167_1172delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406777.1:c.1167_1172delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406778.1:c.1167_1172delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406779.1:c.996_1001delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406780.1:c.996_1001delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406781.1:c.996_1001delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406782.1:c.996_1001delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406783.1:c.867_872delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406784.1:c.903_908delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406785.1:c.876_881delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406786.1:c.867_872delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406788.1:c.708_713delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406789.1:c.708_713delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406790.1:c.708_713delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406791.1:c.588_593delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406792.1:c.444_449delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406793.1:c.444_449delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_001406794.1:c.444_449delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_020629.2:c.1893_1898delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_020630.7:c.1893_1898delCGAGCT - inframe_indel - [Sequence Ontology: SO:0001820]
  • NM_020975.6:c.1893_1898del - inframe_indel - [Sequence Ontology: SO:0001820]
Functional consequence:
Uncertain function

Condition(s)

Name:
MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB (MEN2B)
Synonyms:
MEN IIB; NEUROMATA, MUCOSAL, WITH ENDOCRINE TUMORS; MULTIPLE ENDOCRINE NEOPLASIA, TYPE III; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008082; MeSH: D018814; MedGen: C0025269; Orphanet: 653; OMIM: 162300

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001443814Division of Medical Genetics, Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi
criteria provided, single submitter

(Submitter's publication)		Likely pathogenic
(Nov 19, 2020) 		de novoclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novoyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Division of Medical Genetics, Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi, SCV001443814.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providedclinical testingnot provided

Description

The p.Asp631_Leu633delinsGlu variant, not reported in population databases, was identified in a female child with a clinical picture resembling the MEN2B phenotype. Segregation analysis undertaken in the family demonstrated that it occurred "de novo". This variant is very similar to a somatic in-frame deletion studied by Borganzone et al (1999), p.Glu632_Leu633del (c.1894_1899delGAGCTG), that reduces the spacing between two Cysteine residues, causing ligand-independent constitutive dimerization and activation of RET. Although in the p.Asp631_Leu633delinsGlu variant the deletion is shifted by 1 bp compared to the alteration described by Borganzone et al, it results in the deletion of two amino acids in the same location: thus, the final effect, that is the constitutive activation of RET signaling, is likely to be the same. Collectively taken, the "de novo" origin in the patient, her clinical phenotype, and the functional data support the hypothesis that the p.Asp631_Leu633delinsGlu variant is causative of MEN2B and should be assigned to the HST/H risk class.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 20, 2024