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

gnomAD frequency: 0.00039  dbSNP: rs148935214

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001082257	SCV000166611	likely benign	Multiple endocrine neoplasia, type 2	2024-01-31	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	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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, Mass General Brigham 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, part of Exact Sciences	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	benign	Multiple endocrine neoplasia, type 2a	2023-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224141	SCV001147868	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	RET: BS2
Illumina Laboratory Services, Illumina	RCV001104572	SCV001261446	likely benign	Hirschsprung disease, susceptibility to, 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 Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000224141	SCV002011456	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121978	SCV002066195	likely benign	not specified	2022-01-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163375	SCV002529958	likely benign	Hereditary cancer-predisposing syndrome	2021-06-21	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000224141	SCV002541060	uncertain significance	not provided	2022-08-31	criteria provided, single submitter	clinical testing	BS1, BP2, PP3
Myriad Genetics, Inc.	RCV000663272	SCV004018072	likely benign	Multiple endocrine neoplasia, type 2a	2023-04-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000224141	SCV004220038	likely benign	not provided	2016-02-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001082257	SCV004357237	likely benign	Multiple endocrine neoplasia, type 2	2022-11-18	criteria provided, single submitter	clinical testing
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