NM_020975.6(RET):c.2522C>T (p.Pro841Leu) AND Multiple endocrine neoplasia, type 2

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000691895.18

Allele description

NM_020975.6(RET):c.2522C>T (p.Pro841Leu)

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.2522C>T (p.Pro841Leu)

HGVS:

NC_000010.11:g.43119660C>T
NG_007489.1:g.47592C>T
NM_000323.2:c.2522C>T
NM_001355216.2:c.1760C>T
NM_001406743.1:c.2522C>T
NM_001406744.1:c.2522C>T
NM_001406759.1:c.2522C>T
NM_001406760.1:c.2522C>T
NM_001406761.1:c.2393C>T
NM_001406762.1:c.2393C>T
NM_001406763.1:c.2387C>T
NM_001406764.1:c.2393C>T
NM_001406765.1:c.2387C>T
NM_001406766.1:c.2234C>T
NM_001406767.1:c.2234C>T
NM_001406768.1:c.2258C>T
NM_001406769.1:c.2126C>T
NM_001406770.1:c.2234C>T
NM_001406771.1:c.2084C>T
NM_001406772.1:c.2126C>T
NM_001406773.1:c.2084C>T
NM_001406774.1:c.1997C>T
NM_001406775.1:c.1796C>T
NM_001406776.1:c.1796C>T
NM_001406777.1:c.1796C>T
NM_001406778.1:c.1796C>T
NM_001406779.1:c.1625C>T
NM_001406780.1:c.1625C>T
NM_001406781.1:c.1625C>T
NM_001406782.1:c.1625C>T
NM_001406783.1:c.1496C>T
NM_001406784.1:c.1532C>T
NM_001406785.1:c.1505C>T
NM_001406786.1:c.1496C>T
NM_001406787.1:c.1490C>T
NM_001406788.1:c.1337C>T
NM_001406789.1:c.1337C>T
NM_001406790.1:c.1337C>T
NM_001406791.1:c.1217C>T
NM_001406792.1:c.1073C>T
NM_001406793.1:c.1073C>T
NM_001406794.1:c.1073C>T
NM_020629.2:c.2522C>T
NM_020630.7:c.2522C>T
NM_020975.6:c.2522C>TMANE SELECT
NP_000314.1:p.Pro841Leu
NP_001342145.1:p.Pro587Leu
NP_001342145.1:p.Pro587Leu
NP_001393672.1:p.Pro841Leu
NP_001393673.1:p.Pro841Leu
NP_001393688.1:p.Pro841Leu
NP_001393689.1:p.Pro841Leu
NP_001393690.1:p.Pro798Leu
NP_001393691.1:p.Pro798Leu
NP_001393692.1:p.Pro796Leu
NP_001393693.1:p.Pro798Leu
NP_001393694.1:p.Pro796Leu
NP_001393695.1:p.Pro745Leu
NP_001393696.1:p.Pro745Leu
NP_001393697.1:p.Pro753Leu
NP_001393698.1:p.Pro709Leu
NP_001393699.1:p.Pro745Leu
NP_001393700.1:p.Pro695Leu
NP_001393701.1:p.Pro709Leu
NP_001393702.1:p.Pro695Leu
NP_001393703.1:p.Pro666Leu
NP_001393704.1:p.Pro599Leu
NP_001393705.1:p.Pro599Leu
NP_001393706.1:p.Pro599Leu
NP_001393707.1:p.Pro599Leu
NP_001393708.1:p.Pro542Leu
NP_001393709.1:p.Pro542Leu
NP_001393710.1:p.Pro542Leu
NP_001393711.1:p.Pro542Leu
NP_001393712.1:p.Pro499Leu
NP_001393713.1:p.Pro511Leu
NP_001393714.1:p.Pro502Leu
NP_001393715.1:p.Pro499Leu
NP_001393716.1:p.Pro497Leu
NP_001393717.1:p.Pro446Leu
NP_001393718.1:p.Pro446Leu
NP_001393719.1:p.Pro446Leu
NP_001393720.1:p.Pro406Leu
NP_001393721.1:p.Pro358Leu
NP_001393722.1:p.Pro358Leu
NP_001393723.1:p.Pro358Leu
NP_065680.1:p.Pro841Leu
NP_065681.1:p.Pro841Leu
NP_065681.1:p.Pro841Leu
NP_065681.1:p.Pro841Leu
NP_066124.1:p.Pro841Leu
NP_066124.1:p.Pro841Leu
LRG_518t1:c.2522C>T
LRG_518t2:c.2522C>T
LRG_518:g.47592C>T
LRG_518p1:p.Pro841Leu
LRG_518p2:p.Pro841Leu
NC_000010.10:g.43615108C>T
NM_001355216.1:c.1760C>T
NM_020630.4:c.2522C>T
NM_020630.6:c.2522C>T
NM_020975.4:c.2522C>T

Protein change:

P358L

Links:

dbSNP: rs149891333

NCBI 1000 Genomes Browser:

rs149891333

Molecular consequence:

NM_000323.2:c.2522C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.1760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.2522C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.2522C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.2522C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.2522C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.2393C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.2393C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.2387C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.2393C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.2387C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.2234C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.2234C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.2258C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.2126C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.2234C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.2084C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.2126C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.2084C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.1997C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.1796C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.1796C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.1796C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.1796C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.1625C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.1625C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.1625C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.1625C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.1496C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.1532C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.1505C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.1496C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406787.1:c.1490C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406788.1:c.1337C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406789.1:c.1337C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406790.1:c.1337C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406791.1:c.1217C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406792.1:c.1073C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406793.1:c.1073C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406794.1:c.1073C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.2522C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.2522C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.2522C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Multiple endocrine neoplasia, type 2 (MEN2)
Identifiers:: MONDO: MONDO:0019003; MedGen: C4048306

Recent activity

Clear Turn Off Turn On

sorting nexin-6 [Rattus norvegicus]
sorting nexin-6 [Rattus norvegicus]
gi|157823311|ref|NP_001102181.1|

Protein
Viburnum opulus var. sargentii isolate DW17 ribulose 1,5-bisphosphate carboxylas...
Viburnum opulus var. sargentii isolate DW17 ribulose 1,5-bisphosphate carboxylase (rbcL) gene, partial cds; chloroplast
gi|371928296|gb|HQ591762.1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000819693	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 27, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22648184, 24134185, 26071011, 28492532
SCV001775523	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Uncertain significance (Jul 29, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000819693

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 27, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001775523

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Uncertain significance
(Jul 29, 2021)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hirschsprung's disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation.

Carter TC, Kay DM, Browne ML, Liu A, Romitti PA, Kuehn D, Conley MR, Caggana M, Druschel CM, Brody LC, Mills JL.

J Hum Genet. 2012 Aug;57(8):485-93. doi: 10.1038/jhg.2012.54. Epub 2012 May 31.

PubMed [citation]

PMID:: 22648184
PMCID:: PMC3503526

Germline mutations and genotype-phenotype correlations in patients with apparently sporadic pheochromocytoma/paraganglioma in Korea.

Kim JH, Seong MW, Lee KE, Choi HJ, Ku EJ, Bae JH, Park SS, Choi SH, Kim SW, Shin C, Kim SY.

Clin Genet. 2014 Nov;86(5):482-6. doi: 10.1111/cge.12304. Epub 2013 Nov 15.

PubMed [citation]

PMID:: 24134185

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000819693.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 841 of the RET protein (p.Pro841Leu). This variant is present in population databases (rs149891333, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of multiple endocrine neoplasia type 2 or Hirschsprung's disease (PMID: 22648184, 24134185, 26071011). ClinVar contains an entry for this variant (Variation ID: 24947). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV001775523.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The RET c.2522C>T (p.Pro841Leu) missense change has a maximum subpopulation frequency of 0.060% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/10-43615108-C-T). This is higher than the reported incidence of multiple endocrine neoplasia type 2 (BS1). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in individuals with clinical features of multiple endocrine neoplasia type 2 or Hirschsprung's disease (PS4_supporting; PMID: 22648184, 24134185, 26071011). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS1, PS4_supporting, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 16, 2024

ClinVar

Relating variation to medicine