ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1946C>T (p.Ser649Leu) (rs148935214)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001082257 SCV000166611 likely benign Multiple endocrine neoplasia, type 2 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163375 SCV000213915 likely benign Hereditary cancer-predisposing syndrome 2019-04-19 criteria provided, single submitter clinical testing Conflicting evidence
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224141 SCV000281200 benign not provided 2016-05-06 criteria provided, single submitter clinical testing
GeneDx RCV000121978 SCV000514408 likely benign not specified 2016-01-26 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000121978 SCV000540172 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been classified as DM in HGMD related to elevated basal serum calcitonin. It has been reported in 12 papers, with 2 related to Hirschprung disease. The comments suggest that it is not pathogenic. This variant is present at 0.05% in ExAC. It is classified in ClinVar with 1 star as Likely benign/Benign by Invitae and Children's Mercy Hospital, and as VUS by Ambry and ARUP. Variant occurs at greater frequency in population than expected for disorder
Counsyl RCV000663272 SCV000786504 likely benign Multiple endocrine neoplasia, type 2a 2018-05-16 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000224141 SCV000807017 likely benign not provided 2017-05-04 criteria provided, single submitter clinical testing
GeneKor MSA RCV000163375 SCV000822193 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000663272 SCV000838393 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224141 SCV001147868 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001104572 SCV001261446 likely benign Hirschsprung disease 1 2018-05-15 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV001104573 SCV001261447 uncertain significance Pheochromocytoma 2018-05-15 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001104574 SCV001261448 benign Multiple endocrine neoplasia 2018-05-15 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001104575 SCV001261449 likely benign Renal hypodysplasia/aplasia 1 2018-05-15 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121978 SCV001821367 likely benign not specified 2021-08-23 criteria provided, single submitter clinical testing Variant summary: RET c.1946C>T (p.Ser649Leu) results in a non-conservative amino acid change in 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 0.00034 in 251656 control chromosomes. The observed variant frequency is approximately 61 fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma phenotype (5.6e-06), strongly suggesting that the variant is benign. c.1946C>T has been reported in the literature in individuals affected with sporadic/familial Medullary Thyroid Carcinoma/Hirschsprung's disease and in some instances in unaffected family members when tested (example, Wiench_2001, Vierhapper_2004, Colombo-Benkmann_2008, deGroot_2006, Vaclavikova_2009, Waldman_2009, Erlic_2010, Innella_2020). These data do not allow any conclusion about variant significance. Multiple co-occurrences in trans with other pathogenic variant(s) have been reported in the citations ascertained above (example, RET c.1902C>G, p.Cys634Trp; RET c.1901G>A, p.Cys634Tyr; RET c.2410G>A, p.Val804Met; RET c.2410G>C, p.Val804Leu), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Colombo-Benkmann_2008). The most pronounced variant effect results in a mild transforming potential and constitutive TK activity, and stimulation of growth of NIH3T3 cells. This resulted in its classification as a level 1 RET variant, namely low penetrance of MTC, a relatively low aggressive potential of the disease (level 1), and rare further endocrinopathies. In summary, this was historically considered a "mild" mutation in MTC since penetrance seemed quite low, disease phenotype was milder than in MEN2/2A, and prognosis was good in patients with this variant; however, the interpretation changed when Erlic_2010 reported data strongly suggesting it is NOT pathogenic: 1) variant was incidentally found in the healthy sister of a p.C634Y MTC/PHEO patient during family testing for p.C634Y; 2) variant was found at significant frequencies in European and American normals. The non-pathogenicity of this variant is supported by the fact that in multiple reported MTC cases, it has co-occurred with true pathogenic variants, with reports that the two mutations together did not aggravate disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments but a majority concordance towards a benign/likely benign outcome (n=8) (VUS, n=6). Based on the evidence outlined above, the variant was classified as likely benign.
Research and Development, ARUP Laboratories RCV000121978 SCV000055379 uncertain significance not specified 2018-05-04 no assertion criteria provided literature only PMID 19906784 and 29656518 indicates p.S649L is a rare non-pathogenic polymorphism rather than a disease-causing mutation. GnomAD frequency 0.033%, fairly common for uncommon disease (gnomad.broadinstitute.org/gene/ENSG00000165731). If mutation, p.S649L may have low or variable penetrance. Four individual reports: 2 MTC only, 1 HPT only (24 yr), 1 elevated calcitonin (47 yr). First family report, 5 have the variant genotype: 1 MTC only (69 yr). Second family report, 3 have the variant genotype: 2 asymptomatic (75, 41 yr), 1 elevated calcitonin (43 yr). In vitro studies (PMID 18322301). Additional references: PMID 15320968, 21551259, and MEN2 meeting poster P20 http://www.hormones.gr/preview.php?c_id=622. Has been found with other RET changes, see c.[1900T>C];[1946C>T], c.[1902C>G];[1946C>T] and c.1946C>T(;)2372A>T.
ITMI RCV000121978 SCV000086187 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148770 SCV000190507 likely benign Elevated basal serum calcitonin 2014-06-01 no assertion criteria provided research
Klinik und Poliklinik für Kinderchirurgie,Technische Universität Dresden, Universitätsklinikum Carl Gustav Carus RCV001533539 SCV001469009 uncertain significance Appendicitis 2020-12-17 no assertion criteria provided research

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