ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2410G>T (p.Val804Leu) (rs79658334)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000354366 SCV000329834 pathogenic not provided 2018-09-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted RET c.2410G>T at the cDNA level, p.Val804Leu (V804L) at the protein level, and results in the change of a Valine to a Leucine (GTG>TTG). This variant has been reported many times in association with familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia type 2A (MEN2A) (Eng 1997, Nilsson 1999, Lombardo 2002, Romei 2010, Curras-Freixes 2015). Functional studies show that RET Val804Leu results in gain-of-function by way of ligand-independent autophosphorylation (Pasini 1997, Carlomagno 2004). However, the transforming capacity of this variant has been reported to be lower than that of other MEN2A and MEN2B pathogenic variants (Pasini 1997, Iwashita 1999). Of note, variants involving the Valine at residue 804 are considered to be level A variants by the American Thyroid Association, meaning they are associated with a lower risk of medullary thyroid cancer in comparison with other more penetrant pathogenic variants in the RET gene (Figlioli 2013, Hedayati 2016). RET Val804Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the tyrosine kinase domain (Garcia-Barcelo 2004). In silico analyses, which include protein predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. Based on currently available evidence, we consider this variant to be pathogenic.
GenePathDx,Causeway Health Care Private Ltd RCV000487450 SCV000574540 pathogenic Familial medullary thyroid carcinoma; Multiple endocrine neoplasia 2016-10-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000354366 SCV000605022 pathogenic not provided 2017-08-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000561258 SCV000674843 pathogenic Hereditary cancer-predisposing syndrome 2018-12-13 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Other strong data supporting pathogenic classification
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000354366 SCV000705164 pathogenic not provided 2017-01-10 criteria provided, single submitter clinical testing
Counsyl RCV000596480 SCV000786135 pathogenic Multiple endocrine neoplasia, type 2a 2018-03-02 criteria provided, single submitter clinical testing
Invitae RCV000021854 SCV000824152 pathogenic Multiple endocrine neoplasia, type 2 2019-10-15 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 804 of the RET protein (p.Val804Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs79658334, ExAC 0.003%). This variant was reported to segregate with medullary thyroid carcinoma (MTC) in several families (PMID: 7784092, 16343097, 10235148) and has been observed in numerous individuals and families with MTC and pheochromocytoma (PMID: 10235148, 15741265, 26269449, 18058472, 18062802, 21626080). This variant is referred as a Level A variant, representing the lowest MTC risk group of RET variants, by the American Thyroid Association (PMID: 25810047, 19469690). ClinVar contains an entry for this variant (Variation ID: 13946). Experimental studies have shown that this missense change induces cellular transformation and differentiation in vitro although the transforming activity is lower than other RET mutations (PMID: 9242375, 10445857). In addition, this variant confers certain resistance to several tyrosine kinase inhibitors (PMID: 16507829, 26046350). A different missense substitution at this codon (p.Val804Met) has been determined to be pathogenic (PMID: 8797874, 9452077, 10876191). This suggests that the valine residue is critical for RET protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000354366 SCV000842755 pathogenic not provided 2017-11-30 criteria provided, single submitter clinical testing
OMIM RCV000014973 SCV000035229 pathogenic Familial medullary thyroid carcinoma 2005-06-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000021854 SCV000055398 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only The 12 yr old with metastatic MTC also had somatic p.M918T mutation (PMID 11932300). Youngest with HPT: 9 yr (PMID 16813623). FMTC phenotype is more common, only three family reports of MEN2A (PMID 16813623, 10235148 and 16343097) and one report of homozygous mutation causing MEN2A (PMID 15741265). In vitro studies: RET activation (PMID 9242375 and 10445857). Additional references: PMID 20497437, 11114642 and 9384613. Has been found with another RET change, see c.[2372A>T];[2410G>T].

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