chr10-43121968-T-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_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 project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
RET
NM_020975.6 missense
NM_020975.6 missense
Scores
14
2
3
Clinical Significance
Conservation
PhyloP100: 8.01
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 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RET | NM_020975.6 | c.2753T>C | p.Met918Thr | missense_variant | 16/20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RET | ENST00000355710.8 | c.2753T>C | p.Met918Thr | missense_variant | 16/20 | 5 | NM_020975.6 | ENSP00000347942 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251478Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135922
GnomAD3 exomes
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1
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251478
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1
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135922
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GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:42
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:12
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jul 03, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 13, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 24, 2019 | Widely 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, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 19, 2022 | Most 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 submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 29, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 25, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 30, 2022 | PP4, PP5, PM1, PM2, PS3, PS4_moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Nov 10, 2023 | - - |
Multiple endocrine neoplasia type 2B Pathogenic:9
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 07, 1998 | - - |
| Pathogenic, criteria provided, single submitter | research | Duke University Health System Sequencing Clinic, Duke University Health System | Apr 20, 2023 | - - |
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 08, 2021 | Variant 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, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | May 23, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Nov 03, 2006 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 11, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 18, 2023 | This 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 submitter | clinical testing | Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS) | May 21, 2023 | - - |
Multiple endocrine neoplasia type 2A Pathogenic:4
| Pathogenic, criteria provided, single submitter | research | Department of Pediatrics, Memorial Sloan Kettering Cancer Center | Dec 15, 2020 | - - |
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 21, 2016 | M918T is associated only with MEN2B phenotype. - |
Hirschsprung disease, susceptibility to, 1 Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 29, 2024 | - - |
Familial medullary thyroid carcinoma Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 17, 2018 | This 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 submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Dec 23, 2022 | - - |
Medullary thyroid carcinoma Pathogenic:2
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Mar 10, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3DMed Clinical Laboratory Inc | Aug 02, 2017 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 11, 2022 | The 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. - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 01, 2021 | - - |
Multiple endocrine neoplasia type 4 Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
Pheochromocytoma Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 07, 1998 | - - |
Multiple endocrine neoplasia, type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2023 | This 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 disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 21, 2024 | The 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 submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 16, 2019 | The 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. - |
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 submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 08, 2014 | - - |
Multiple endocrine neoplasia, type 1 Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
Thyroid carcinoma, sporadic medullary Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 07, 1998 | - - |
Thyroid tumor Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Loss of MoRF binding (P = 0.1062);Loss of MoRF binding (P = 0.1062);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at