Submissions for variant NM_020975.6(RET):c.2944C>T (p.Arg982Cys)

gnomAD frequency: 0.01567  dbSNP: rs17158558

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082055	SCV000113994	benign	not specified	2014-10-23	criteria provided, single submitter	clinical testing
Invitae	RCV001080524	SCV000153846	benign	Multiple endocrine neoplasia, type 2	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162949	SCV000213436	benign	Hereditary cancer-predisposing syndrome	2014-11-24	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
GeneDx	RCV000082055	SCV000234928	benign	not specified	2016-09-23	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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202663	SCV000258172	benign	Multiple endocrine neoplasia	2015-04-17	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000162949	SCV000267090	benign	Hereditary cancer-predisposing syndrome	2016-02-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000082055	SCV000269746	benign	not specified	2015-12-09	criteria provided, single submitter	clinical testing	p.Arg982Cys in exon 18 of RET: This variant is not expected to have clinical sig nificance because it is not located within the splice consensus sequence. It has been identified in 4% (666/16512) of South Asian chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs17158558).
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238890	SCV000297299	benign	Familial medullary thyroid carcinoma	2015-09-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000082055	SCV000313724	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000202663	SCV000362376	likely benign	Multiple endocrine neoplasia	2017-04-27	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	RCV000354936	SCV000362377	likely benign	Renal hypodysplasia/aplasia 1	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000014965	SCV000362378	likely benign	Hirschsprung disease, susceptibility to, 1	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000320112	SCV000362379	likely benign	Pheochromocytoma	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Counsyl	RCV000410308	SCV000489799	benign	Multiple endocrine neoplasia, type 2b	2016-04-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000411820	SCV000489800	benign	Multiple endocrine neoplasia, type 2a	2016-04-05	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000411820	SCV000782261	uncertain significance	Multiple endocrine neoplasia, type 2a	2016-11-01	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000034774	SCV000842760	benign	not provided	2017-12-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000082055	SCV001363345	benign	not specified	2019-12-23	criteria provided, single submitter	clinical testing	Variant summary: RET c.2944C>T (p.Arg982Cys) results in a non-conservative amino acid change located in the serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.019 in 251460 control chromosomes in the gnomAD database, including 78 homozygotes. The observed variant frequency is approximately 1299 fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2/Hirschsprung Disease phenotype (1.5e-05), strongly suggesting that the variant is benign. c.2944C>T has been reported in the early literature predating large control datasets in individuals reportedly affected with Multiple Endocrine Neoplasia Type 2/Hirschsprung Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Multiple Endocrine Neoplasia Type 2/Hirschsprung Disease with no evidence supporting a damaging outcome in subsequent literature relating to this specific variant. At-least two co-occurrences with other pathogenic variant(s) have been reported (RET c.1852T>C, p.Cys618Arg; RET c.2410G>A, p.Val804Met), providing supporting evidence for a benign role (Mulligan_1994, and Lesueur_2005). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant Pasini_1995. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=7, likely benign, n=1, VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034774	SCV002048343	benign	not provided	2023-10-27	criteria provided, single submitter	clinical testing
Department of Human Genetics, Hannover Medical School	RCV001822995	SCV002072583	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2022-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034774	SCV002497027	benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	RET: BP4, BS1, BS2
Sema4, Sema4	RCV000162949	SCV002529995	benign	Hereditary cancer-predisposing syndrome	2020-10-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000082055	SCV002550393	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000410308	SCV004017339	benign	Multiple endocrine neoplasia, type 2b	2023-07-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001080524	SCV004357254	benign	Multiple endocrine neoplasia, type 2	2022-06-09	criteria provided, single submitter	clinical testing
OMIM	RCV000014965	SCV000035221	risk factor	Hirschsprung disease, susceptibility to, 1	1998-08-01	no assertion criteria provided	literature only
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034774	SCV000043479	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000082055	SCV000086193	not provided	not specified	2013-09-19	no assertion provided	reference population
Human Genomics Unit, Institute for molecular medicine Finland (FIMM)	RCV000736279	SCV000864577	uncertain significance	Aganglionic megacolon	2013-01-01	no assertion criteria provided	research
Center of Medical Genetics and Primary Health Care	RCV001269493	SCV001449149	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000082055	SCV001742225	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000082055	SCV001807964	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000082055	SCV001926276	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000082055	SCV001952506	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000034774	SCV002036341	likely benign	not provided		no assertion criteria provided	clinical testing