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rs74799832

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_020975.6(RET):c.2753T>C(p.Met918Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M918V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

RET
NM_020975.6 missense

Scores

14
2
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:40

Conservation

PhyloP100: 8.01
Variant links:
Genes affected
RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr10-43121967-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38614.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=1, Uncertain_significance=1}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 10-43121968-T-C is Pathogenic according to our data. Variant chr10-43121968-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43121968-T-C is described in Lovd as [Pathogenic]. Variant chr10-43121968-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RETNM_020975.6 linkuse as main transcriptc.2753T>C p.Met918Thr missense_variant 16/20 ENST00000355710.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RETENST00000355710.8 linkuse as main transcriptc.2753T>C p.Met918Thr missense_variant 16/205 NM_020975.6 P4P07949-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251478
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:40
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:11
Pathogenic, criteria provided, single submitterclinical testingAthena Diagnostics IncJul 24, 2019Widely published variant reported to account for 95% of MEN2B cases. The best available variant frequency is uninformative because there are too few occurrences in population data. Found in multiple symptomatic patients. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Multiple de novo cases reported in the literature. In familial cases, variant segregates with disease. -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalJul 03, 2015- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJun 30, 2022PP4, PP5, PM1, PM2, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJan 13, 2017- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityOct 25, 2021- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 19, 2022Most common RET variant reported in association with MEN2B (Carlson 1994, Eng 1996, Brauckhoff 2004, Wray 2008); Published functional studies demonstrate a damaging effect: increased transforming ability, cellular proliferation, and tyrosine phosphorylation (Pasini 1997, Cosci 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10679286, 8570194, 30763276, 20516206, 15517484, 22359510, 10369718, 26843961, 23225389, 30660595, 18252215, 19826964, 11720239, 21765987, 9242375, 21810974, 7906417, 24336963, 23660265, 26294908, 23660872, 8918855, 7824936, 27807060, 27539324, 17963006, 29182461, 17540634, 19169500, 29396759, 16481266, 9541448, 18631354, 17576593, 17848262, 16808642, 26084817, 31510104, 29625052, 34308366, 33268590, 32561571, 8909322, 9706252, 33191720, 30624503, 32546069, 14633923) -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 29, 2016- -
Multiple endocrine neoplasia, type 2b Pathogenic:8
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalNov 03, 2006- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterAug 11, 2021- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 08, 2021Variant summary: RET c.2753T>C (p.Met918Thr) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251618 control chromosomes. c.2753T>C has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2B (example, Carlson_1994, Elisei_2007, Hofstra_1994). These data indicate that the variant is very likely to be associated with disease. Multiple publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significant increase in tyrosine kinase activity resulting in a transforming activation of the RET proto-oncogene (example, Borrello_1995). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Apr 18, 2023This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16715139, 9242375, 21810974]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7906417, 34629742, 29656518, 34881033, 25810047]. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)May 21, 2023- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 07, 1998- -
Pathogenic, criteria provided, single submitterresearchDuke University Health System Sequencing Clinic, Duke University Health SystemApr 20, 2023- -
Multiple endocrine neoplasia, type 2a Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Pathogenic, criteria provided, single submitterresearchDepartment of Pediatrics, Memorial Sloan Kettering Cancer CenterDec 15, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCounsylOct 21, 2016M918T is associated only with MEN2B phenotype. -
Familial medullary thyroid carcinoma Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsDec 17, 2018This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 7906417, 17540634, 8570194, 19169500, 22359510, 21810974, 23660872, 24336963, 21765987] -
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyDec 23, 2022- -
Medullary thyroid carcinoma Pathogenic:2
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Mar 10, 2016- -
Pathogenic, criteria provided, single submitterclinical testing3DMed Clinical Laboratory IncAug 02, 2017- -
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submittercurationSema4, Sema4Jul 01, 2021- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 11, 2022The p.M918T pathogenic mutation (also known as c.2753T>C), located in coding exon 16 of the RET gene, results from a T to C substitution at nucleotide position 2753. The methionine at codon 918 is replaced by threonine, an amino acid with similar properties. This mutation is located in the catalytic core of the tyrosine kinase domain, within a highly conserved region of the RET protein. This mutation was first described in 58 individuals with a clinical diagnosis of multiple endocrine neoplasia type 2B (MEN2B) (Carlson KM et al. Proc. Natl. Acad. Sci. U.S.A. 1994;91(4):1579-83), and has since been well described in numerous other affected individuals (Choi S et al. PLoS Genet. 2012;8(2):e1002420; Hedayati M et al. J Thyroid Res. 2011;2011:264248; Smith V et al. Gut. 1999 Jul;45(1):143-6). In another study, this mutation was described in 95% (75/79) of MEN2B families (Eng C et al. JAMA 1996;276(19):1575-9). Per the revised American Thyroid Associated guidelines, individuals with alterations at codon 918 in the RET gene are at highest risk for MTC with recommended screenings and/or surgical interventions beginning in early childhood (Wells SA et al. Thyroid 2015 Jun; 25(6):567-610). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Multiple endocrine neoplasia type 4 Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 06, 2014- -
Pheochromocytoma Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 07, 1998- -
Hirschsprung disease, susceptibility to, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGenomics England Pilot Project, Genomics England-- -
Multiple endocrine neoplasia, type 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 22, 2023This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 918 of the RET protein (p.Met918Thr). This variant is present in population databases (rs74799832, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant multiple endocrine neoplasia type 2 (PMID: 7906417, 8918855, 16715139, 20516206, 27539324). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13919). 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 disruptive. Experimental studies have shown that this missense change affects RET function (PMID: 8570194, 9242375, 16715139, 21810974). For these reasons, this variant has been classified as Pathogenic. -
RET-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 21, 2024The RET c.2753T>C variant is predicted to result in the amino acid substitution p.Met918Thr. This variant has previously been reported to be causative for multiple endocrine neoplasia type 2B, medullary thyroid carcinoma, and pheochromocytoma (Carlson et al. 1994. PubMed ID: 7906417; Hedayati et al. 2011. PubMed ID : 21765987; de Cubas et al. 2013. PubMed ID : 23660872; http://www.arup.utah.edu/database/MEN2/). This variant was also shown in vitro to have transforming ability (Pasini et al. 1997. PubMed ID: 9242375; Cosci et al. 2011. PubMed ID: 21810974). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13919/). This variant is interpreted as pathogenic. -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesApr 16, 2019The RET c.2753T>C, p.Met918Thr variant has been reported in multiple patients diagnosed with multiple endocrine neoplasia type 2b (Carlson 1994, Jindrichova 2004), co-segregated with affected family members, or occurred as a de novo alteration (Carlson 1994) and has been reported to confer high risk (Wells 2015). Functional characterization of the variant protein indicates an increase in basal auto-phosphorylation that is further enhanced upon growth factor stimulation, with altered target specificity compared to wildtype protein (Bongarzone 1998, Santoro 1995). The variant is listed in the dbSNP variant database (rs74799832), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Exome Aggregation Consortium). The methionine at residue 918 is highly conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic. References: Bongarzone I et al. Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation. Oncogene. 1998; 16(18):2295-301. Carlson K et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A. 1994; 91(4):1579-83. Jindrichova S et al. Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J Endocrinol. 2004; 183(2):257-65. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995; 267(5196):381-3. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015; 25(6):567-610. -
Multiple endocrine neoplasia, type 1 Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Constipation;C0020534:Hypertelorism;C0020676:Hypothyroidism;C0039685:Tetralogy of Fallot;C0349588:Short stature;C0376480:Gingival overgrowth;C1836543:Thick vermilion border;C1844820:Joint hypermobility Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaDec 08, 2014- -
Thyroid carcinoma, sporadic medullary Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 07, 1998- -
Thyroid tumor Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Oct 02, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
Cadd
Pathogenic
27
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.86
D;.
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.85
T;T
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
0.78
D
MutationAssessor
Benign
1.7
L;L
MutationTaster
Benign
1.0
A;A
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-5.5
D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.99
MutPred
0.99
Loss of MoRF binding (P = 0.1062);Loss of MoRF binding (P = 0.1062);
MVP
0.97
MPC
0.84
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.96
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs74799832; hg19: chr10-43617416; COSMIC: COSV60685905; API