ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2410G>A (p.Val804Met) (rs79658334)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182584 SCV000234936 pathogenic not provided 2018-12-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted RET c.2410G>A at the cDNA level, p.Val804Met (V804M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has been reported to segregate with medullary thyroid cancer in several large families and has also been identified in other unrelated individuals with familial medullary thyroid carcinoma (FMTC) or multiple endocrine neoplasia type 2A (MEN2A) (Fink 1996, Feldman 2000, Gibelin 2004, Recasens 2007, Shifrin 2009, Griffith 2010, Basaran 2015). In vitro focus formation studies indicate that V804M results in increased transforming activity over wild type (Cosci 2011). RET Val804Met was observed at an allele frequency of 0.02% (7/33,678) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located in the tyrosine kinase domain (Garcia-Barcelo 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, we consider this variant to be pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000210181 SCV000266128 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000148773 SCV000290546 pathogenic Multiple endocrine neoplasia, type 2 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 804 of the RET protein (p.Val804Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs79658334, ExAC 0.03%). This variant has been reported to segregate with medullary thyroid carcinoma (MTC) in several families with reduced penetrance compared to other pathogenic variants in the RET gene (PMID: 8797874, 9452077, 10876191, 25501606, 19958926, 11114642, 12019403, 17895320, 25440022). It is referred to by the American Thyroid Association as a Level A variant, representing the lowest MTC risk group of RET variants (PMID: 25810047). The cumulative lifetime risk for MTC in individuals harboring this variant has been calculated to be 17% by age 40, 31% by age 50, 67% by age 60, and 87% by age 70 (PMID: 24617864). Notably, this variant is not typically associated with pheochromocytoma, parathyroid adenoma or hyperparathyroidism. ClinVar contains an entry for this variant (Variation ID: 37102). Experimental studies have shown that this missense change significantly increases cell viability, migration and tyrosine kinase activity of the RET protein (PMID: 21711375, 20039896). In addition, this missense variant confers resistance to selective kinase inhibitors (PMID: 15184865). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000182584 SCV000344435 pathogenic not provided 2016-08-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999914 SCV000605023 pathogenic not specified 2018-07-23 criteria provided, single submitter clinical testing The RET c.2410G>A; p.Val804Met variant (rs79658334) has been described in individuals affected with multiple endocrine neoplasia type 2 (MEN2), and has shown to segregate with disease but with reduced penetrance compared to different pathogenic RET variants (Basaran 2015, Choi 2013, Elisei 2007, Fattoruso 1998, Feldman 2000, Fink 1996, Romei 2015). It is generally not associated with pheochromocytoma, parathyroid adenoma or hyperparathyroidism, and the American Thyroid Association describes individuals with this variant as having a moderate risk for medullary thyroid cancer (MTC) (Wells 2015). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 37102) and is observed in the general population at an overall frequency of 0.014% (36/259772 alleles) in the Genome Aggregation Database. It is estimated that the cumulative lifetime risk for MTC in individuals harboring this variant is 31% by age 50, 67% by age 60 and 87% by age 70 (Rich 2014), although penetrance has also been estimated to be as low as 4% (Loveday 2018). The valine at residue 804 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict that this variant has an impact on the protein structure and/or function. Additionally, in vitro functional studies demonstrate increased cellular proliferation and tyrosine kinase activity, as well as a conferred resistance to selective kinase inhibitors (Carlomagno 2004, Castellone 2010, Cosci 2011, Machens 2011). Based on available information, this variant is considered pathogenic. References: Basaran M et al. Characterization of V804M-mutated RET proto-oncogene associated with familial medullary thyroid cancer, report of the largest Turkish family. J Endocrinol Invest. 2015 May;38(5):541-6. Carlomango F et al. Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene. 2004 Aug 12;23(36):6056-63. Castellone M et al. A novel de novo germ-line V292M mutation in the extracellular region of RET in a patient with phaeochromocytoma and medullary thyroid carcinoma: functional characterization. Clin Endocrinol (Oxf). 2010 Oct;73(4):529-34. Choi Y et al. A Case of medullary thyroid carcinoma with de novo V804M RET germline mutation. J Korean Med Sci. 2013; 28(1):156-9. Cosci B et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer. 2011; 18(5):603-12. Elisei R et al. RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab. 2007; 92(12):4725-9. Fattoruso O et al. A GTG to ATG novel point mutation at codon 804 in exon 14 of the RET proto-oncogene in two families affected by familial medullary thyroid carcinoma. Hum Mutat. 1998; Suppl 1:S167-71. Feldman G et al. Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation. Surgery. 2000; 128(1):93-8. Fink M et al. Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. Study Group Multiple Endocrine Neoplasia Austria (SMENA)". Int J Cancer. 1996; 69(4):312-6. Loveday C et al. p.Val804Met
Fulgent Genetics,Fulgent Genetics RCV000515232 SCV000611313 pathogenic Congenital central hypoventilation; Hirschsprung disease 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Renal hypodysplasia/aplasia 1; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a 2017-05-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000210181 SCV000674764 pathogenic Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family;Well-characterized mutation at same position;Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Counsyl RCV000499191 SCV000677731 pathogenic Multiple endocrine neoplasia, type 2a 2017-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586783 SCV000699459 pathogenic MEN2 phenotype: Unclassified 2017-08-03 criteria provided, single submitter clinical testing Variant summary: The RET c.2410G>A (p.Val804Met) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 13/63744 control chromosomes at a frequency of 0.0002039. This variant has been reported to have a variable penetrance as the most frequently altered codon in multiple patients with features of FMTC (Familial Medullary Thyroid Cancer) and CCH (C-cell hyperplasia). It must be noted that CCH in MEN2 patients has been implicated as the precursor of in-situ MTC. This variant has also been described in a patient with co-existing germline mutations in NF1. This patient showed features of Neurofibromatosis and CCH. In vitro studies showed that this variant had an effect on RET protein function resulting in a moderately increased transforming activity consistent with its ATA (American Thyroid Association) classification as a low risk variant. Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic while acknolwdging its variable penetrance in patients with FMTC/MTC. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000148773 SCV000711346 pathogenic Multiple endocrine neoplasia, type 2 2017-05-24 criteria provided, single submitter clinical testing The p.Val804Met variant in RET has been reported in > 6 probands with multiple e ndocrine neoplasia type 2 (MEN2), occurring de novo in at least one of these ind ividuals, and segregated with disease in over 25 affected relatives from 5 affec ted families (for examples, see Kasprzak 2001, Shifrin 2009, Shifrin 2010, Nakao 2013, Kihara 2014, Ercolino 2014). The majority of individuals with this varian t have familial medullary thyroid carcinoma, although at least 2 individuals wer e diagnosed with MEN2B. In vitro functional studies provide some evidence that t his variant may impact protein function (Machens 2011, Castellone 2010). The p.V al804Met variant has been classified by the American Thyroid Association as impa rting a moderate risk to developing aggressive medullary thyroid carcinoma (Well s 2015). It has also been reported by other clinical laboratories in ClinVar (Va riation ID #37102). In addition, this variant has been identified in 21/116790 o f European chromosomes by the Genome Aggregation Consortium (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs79658334). In summary, this variant meets criteri a to be classified as pathogenic for MEN2 in an autosomal dominant manner based on presence in multiple affected individuals and segregation studies.
PreventionGenetics,PreventionGenetics RCV000182584 SCV000807027 pathogenic not provided 2016-06-24 criteria provided, single submitter clinical testing
GeneKor MSA RCV000210181 SCV000821780 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This sequence change replaces Valine with Methionine at codon 804 of the RET protein. The valine residue is highly conserved among species in the Protein kinase domain of the protein. There is a small physicochemical difference between valine and methionine (Grantham Score 21). This variant has been described in several families with multiple endocrine neoplasia type 2 and medullary thyroid carcinoma (MTC) (PMID 8797874, 23468374, 9452077, 10876191, 25501606). This variant is listed in population databases at a very low frequency (rs79658334, ExAC 0.03%). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may have a deleterious impact on protein function. Moreover, this prediction has been confirmed experimentally (PMID: 20039896,21711375,) .The mutation database ClinVar contains multiple entries for this variant (Variation ID:37102).
Mendelics RCV000499191 SCV000838401 pathogenic Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000499191 SCV000840056 pathogenic Multiple endocrine neoplasia, type 2a 2017-05-26 criteria provided, single submitter clinical testing This c.2410G>A (p.Val804Met) variant in the RET gene has been reported in multiple publications [PMID 8797874, 20369307, 21810974, 24361808, 23468374, 23341727, 11732489, 24336963, 19958926, 20494215]. This variant was reported in patients and segregating in multiple families with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma [PMID 8797874, 23468374, 23341727, 20369307, 19958926, 20494215]. In vitro analysis showed that this variant affect the function of the RET protein [PMID 21810974]. A different nucleotide change (c.2410G>C), affecting the same amino acid (p.Val804Leu) has also been reported in a patient with multiple endocrine neoplasia 2 [PMID 14718397]. This variant is highly conserved and while not validated for clinical use, computer-based algorithms predict this p.Val804Met change to be deleterious. This variant has been observed in 13 heterozygous individuals in the ExAC database (http://exac.broadinstitute.org/variant/10-43614996-G-A). It is thus classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000182584 SCV001249002 pathogenic not provided 2019-08-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV000148773 SCV000042518 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. 6 yr old had metastatic MTC. p.V804M may have variable penetrance (PMID 10876191 and 11114642). Reports of homozygous mutation (PMID 12019403 and 15741265). Reports of cutaneous lichen amyloidosis and corneal nerve thickening (PMID 20497437 and 19445625). Additional references: PMID 17316110, 19958926, 17466010 and 9452077. Has been found with other RET changes, see c.2304G>T(;)2410G>A, c.[2332G>A;2410G>A], c.[2342A>G;2410G>A], c.[2410G>A;2413G>A], c.[2410G>A;2417A>G], c.[2410G>A;2531G>T], and c.[2410G>A;2711C>G].
CSER _CC_NCGL, University of Washington RCV000148773 SCV000190510 pathogenic Multiple endocrine neoplasia, type 2 2014-06-01 no assertion criteria provided research
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000499191 SCV000590903 likely pathogenic Multiple endocrine neoplasia, type 2a 2017-07-13 no assertion criteria provided clinical testing This variant has been previously reported in patients from various ethnic origins with MTC and the variant has been shown to co-segregate with the disease by Romei C et al in 2015, Basaran MN et al in 2015, Fink M et al in 1996 and Fattoruso et al in 1998.This variant has been reported in the dbSNP database with identification number rs79658334 and in ExAC database with the allele frequency of 0.025%. In the Clin Var database , the clinical significance of this variant has been reported as pathogenic (RCV000148773.3) with respect to MEN2. In silico prediction tools(SIFT, LRT, MutationTaster, PolyPhen-2 and FATHMM) suggests that this variant is probably damaging to protein function.

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