ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2753T>C (p.Met918Thr) (rs74799832)

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Total submissions: 29
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000161926 SCV000211909 pathogenic Multiple endocrine neoplasia, type 2 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 918 of the RET protein (p.Met918Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals and families affected with MEN2B, including many de novo cases (PMID: 7906417, 27539324, 20516206). This variant accounts for approximately 95% of all MEN2B cases reported (PMID: 8918855, 16715139). ClinVar contains an entry for this variant (Variation ID: 13919). Experimental studies have shown that this missense change results in activation of the RET protein, leading to increased transforming capacity and cellular differentiation (PMID: 8570194, 9242375, 21810974, 16715139). For these reasons, this sequence change has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000082054 SCV000226525 pathogenic not provided 2016-11-29 criteria provided, single submitter clinical testing
GeneDx RCV000082054 SCV000234940 pathogenic not provided 2021-06-10 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 (Lek et al., 2016); 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, 14633923, 29625052, 27535533, 32561571, 8909322, 9706252, 33191720)
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415312 SCV000492883 pathogenic Hypertelorism; Tetralogy of Fallot; Short stature; Hypothyroidism; Constipation; Gingival enlargement; 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 Inc 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.
Ambry Genetics RCV001266480 SCV001444655 pathogenic Inborn genetic diseases 2014-06-06 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,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 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.
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
Research and Development, ARUP Laboratories RCV000014941 SCV000055402 pathogenic Multiple endocrine neoplasia, type 2b 2018-05-04 no assertion criteria provided literature only p.M918T accounts for ~94% of known MEN2B mutations. Youngest age of onset for MTC is 9 weeks (PMID 17848262 and 22992277), Pheo 12 yr. In vitro studies: high RET activation (PMID 7824936, 9242375, 10679286, 10445857). In the oldest reference, codon 918 was called codon 664. Additional references: PMID 19240193, 8880581, 15281979 and 7906417. Has been found with other RET changes; see c.[2372A>T;2753T>C] and c.[2753T>C;2765C>A].
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 Neoplasm of the thyroid gland 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
Human Genetics - Radboudumc,Radboudumc RCV000082054 SCV001951822 pathogenic not provided no assertion criteria provided clinical testing

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