Submissions for variant NM_020975.6(RET):c.2753T>C (p.Met918Thr)

dbSNP: rs74799832

Total submissions: 41

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000161926	SCV000211909	pathogenic	Multiple endocrine neoplasia, type 2	2023-12-22	criteria provided, single submitter	clinical testing	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.
Eurofins Ntd Llc (ga)	RCV000082054	SCV000226525	pathogenic	not provided	2016-11-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000082054	SCV000234940	pathogenic	not provided	2022-03-19	criteria provided, single submitter	clinical testing	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)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415312	SCV000492883	pathogenic	Hypertelorism; Tetralogy of Fallot; Short stature; Hypothyroidism; Constipation; Gingival overgrowth; Joint hypermobility; Thick vermilion border	2014-12-08	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000082054	SCV000510661	pathogenic	not provided	2017-01-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999916	SCV000605028	pathogenic	not specified	2019-04-16	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000175096	SCV000677723	pathogenic	Multiple endocrine neoplasia type 2A	2016-10-21	criteria provided, single submitter	clinical testing	M918T is associated only with MEN2B phenotype.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000175096	SCV000782260	pathogenic	Multiple endocrine neoplasia type 2A	2016-11-01	criteria provided, single submitter	clinical testing
3DMed Clinical Laboratory Inc	RCV000417859	SCV000804060	pathogenic	Medullary thyroid carcinoma	2017-08-02	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000082054	SCV000842759	pathogenic	not provided	2019-07-24	criteria provided, single submitter	clinical testing	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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000082054	SCV001450291	pathogenic	not provided	2015-07-03	criteria provided, single submitter	clinical testing
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000175096	SCV001478177	pathogenic	Multiple endocrine neoplasia type 2A	2020-12-15	criteria provided, single submitter	research
Baylor Genetics	RCV001292662	SCV001481264	pathogenic	Familial medullary thyroid carcinoma	2018-12-17	criteria provided, single submitter	clinical testing	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]
Genomics England Pilot Project, Genomics England	RCV001542764	SCV001760250	likely pathogenic	Hirschsprung disease, susceptibility to, 1		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000014941	SCV001821474	pathogenic	Multiple endocrine neoplasia type 2B	2021-08-08	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000082054	SCV002020786	pathogenic	not provided	2021-10-25	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000082054	SCV002522521	pathogenic	not provided	2022-06-30	criteria provided, single submitter	clinical testing	PP4, PP5, PM1, PM2, PS3, PS4_moderate
Sema4, Sema4	RCV002255998	SCV002529992	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-01	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000014941	SCV002579378	pathogenic	Multiple endocrine neoplasia type 2B	2021-08-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002255998	SCV002750282	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	clinical testing	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.
Duke University Health System Sequencing Clinic, Duke University Health System	RCV000014941	SCV003918924	pathogenic	Multiple endocrine neoplasia type 2B	2023-04-20	criteria provided, single submitter	research
Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	RCV000014941	SCV003930405	pathogenic	Multiple endocrine neoplasia type 2B	2023-05-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000014941	SCV004018499	pathogenic	Multiple endocrine neoplasia type 2B	2023-04-18	criteria provided, single submitter	clinical testing	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].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000082054	SCV004027576	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV001292662	SCV004175521	pathogenic	Familial medullary thyroid carcinoma	2022-12-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532351	SCV004721813	pathogenic	RET-related disorder	2024-02-21	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001542764	SCV004807988	pathogenic	Hirschsprung disease, susceptibility to, 1	2024-03-29	criteria provided, single submitter	clinical testing
OMIM	RCV000014941	SCV000035197	pathogenic	Multiple endocrine neoplasia type 2B	1998-05-07	no assertion criteria provided	literature only
OMIM	RCV000014942	SCV000035198	pathogenic	Thyroid carcinoma, sporadic medullary	1998-05-07	no assertion criteria provided	literature only
OMIM	RCV000014943	SCV000035199	pathogenic	Pheochromocytoma	1998-05-07	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417859	SCV000504363	likely pathogenic	Medullary thyroid carcinoma	2016-03-10	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428538	SCV000504364	pathogenic	Thyroid tumor	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000014941	SCV000510477	likely pathogenic	Multiple endocrine neoplasia type 2B	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444529	SCV000510478	likely pathogenic	Multiple endocrine neoplasia type 4	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425499	SCV000510479	likely pathogenic	Multiple endocrine neoplasia, type 1	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000175096	SCV000510481	likely pathogenic	Multiple endocrine neoplasia type 2A	2016-05-13	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000014941	SCV000804923	pathogenic	Multiple endocrine neoplasia type 2B	2006-11-03	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000082054	SCV001928067	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000082054	SCV001951822	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000082054	SCV001978545	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000014941	SCV004808391	pathogenic	Multiple endocrine neoplasia type 2B	2023-05-23	no assertion criteria provided	clinical testing