NM_020975.4(RET):c.1901G>A (p.Cys634Tyr) AND Multiple endocrine neoplasia, type 2a

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Pathogenic(2) (Last evaluated: May 13, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000014924.22

Allele description [Variation Report for NM_020975.4(RET):c.1901G>A (p.Cys634Tyr)]

NM_020975.4(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_020975.4(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_020630.4:c.1901G>A
  • NM_020975.4:c.1901G>A
  • NP_065681.1: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
  • P07949:p.Cys634Tyr
  • c.1901G>A
Protein change:
C634Y; CYS634TYR
Links:
UniProtKB: P07949#VAR_006325; OMIM: 164761.0004; dbSNP: 75996173
NCBI 1000 Genomes Browser:
rs75996173
Molecular consequence:
  • NM_020975.4:c.1901G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
3

Condition(s)

Name:
Multiple endocrine neoplasia, type 2a (MEN2A)
Synonyms:
MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA
Identifiers:
MeSH: D018813; MedGen: C0025268; Orphanet: 653; OMIM: 171400

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000035180OMIMno assertion criteria providedPathogenic
(May 9, 2002)
germlineliterature only

PubMed (6)
[See all records that cite these PMIDs]

SCV000053074Laboratory Corporation of Americacriteria provided, single submitter
pathogenic
(Aug 18, 2011)
germlinecuration, clinical testing

PubMed (33)
[See all records that cite these PMIDs]

Citation Link,

SCV000510495Database of Curated Mutations (DoCM)no assertion criteria providedLikely pathogenic
(May 13, 2016)
somaticliterature only

PubMed (1)
[See all records that cite this PMID]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes21not providednot provided21not providedliterature only
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknown3not providednot providednot providednot providedclinical testing
not providedsomaticyesnot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains.

Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H.

Oncogene. 1988 Nov;3(5):571-8.

PubMed [citation]
PMID:
3078962

Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B.

Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus MH, et al.

Science. 1995 Jan 20;267(5196):381-3.

PubMed [citation]
PMID:
7824936
See all PubMed Citations (37)

Details of each submission

From OMIM, SCV000035180.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (6)

Description

In affected members of 2 families with MEN2A, Mulligan et al. (1993) found a TGC-to-TAC transition at basepair 1832 of codon 380 resulting in substitution of cysteine to tyrosine (CYS380TYR). (The codon numbered 380 on the basis of the partial RET sequence published by Takahashi et al. (1988) is numbered codon 634 on the basis of the full-length RET sequence (Mulligan et al., 1994).)

Ceccherini et al. (1994) found the cys634-to-tyr (C634Y) mutation in a family with MEN2A associated with primary localized cutaneous lichen amyloidosis (PLCA; see 105250).

Santoro et al. (1995) showed that this mutation is a transforming gene in NIH 3T3 cells as a consequence of constitutive activation of the RET kinase. In MEN2A and familial medullary thyroid carcinoma, point mutations result in the substitution of 1 of the 5 cysteine residues in the extracellular domain of RET. This causes RET dimerization at steady state.

Neumann et al. (2002) identified the C634Y substitution in the germlines of 3 unrelated patients with sporadic pheochromocytoma (171300). The mutation was not identified in 600 control chromosomes.

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

From Laboratory Corporation of America, SCV000053074.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided16not providednot providedcuration PubMed (33)
2not provided3not providednot providedcuration PubMed (33)
3not provided2not providednot providedcuration PubMed (33)
4not providednot providednot providednot providedclinical testing PubMed (33)
5not providednot providednot providednot providedclinical testing PubMed (33)
6not providednot providednot providednot providedclinical testing PubMed (33)

Description

"MEN2A; known common DV; controls not tested."

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes16not providednot provided16not providednot providednot provided
2germlineyes3not providednot provided3not providednot providednot provided
3germlineyes2not providednot provided2not providednot providednot provided
4germlineunknownnot providedBloodassert pathogenicitynot providednot providednot provided See 4
5germlineunknownnot providedBloodassert pathogenicitynot providednot providednot provided See 5
6germlineunknownnot providedBloodassert pathogenicitynot providednot providednot provided See 6

Co-occurrences

#ZygosityAllelesNumber of Observations
4SingleHeterozygoteRET:c.2712C>G, RET:c.2508C>T, RET:c.2307G>T, RET:c.2071G>A, RET:c.135A>G, RET:c.1296A>G1
5SingleHeterozygoteRET:c.2307G>T, RET:c.135A>G, RET:c.1296A>G1
6SingleHeterozygoteRET:c.2307G>T, RET:c.135A>G, RET:c.1296A>G1

From Database of Curated Mutations (DoCM), SCV000510495.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1somaticyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 13, 2017