Submissions for variant NM_020975.6(RET):c.1336G>C (p.Gly446Arg)

gnomAD frequency: 0.00238  dbSNP: rs115423919

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083435	SCV000166601	benign	Multiple endocrine neoplasia, type 2	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162955	SCV000213443	benign	Hereditary cancer-predisposing syndrome	2014-12-23	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Eurofins Ntd Llc (ga)	RCV000121994	SCV000232293	benign	not specified	2015-02-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121994	SCV000313713	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000317413	SCV000362299	benign	Hirschsprung disease, susceptibility to, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000372019	SCV000362300	benign	Pheochromocytoma	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000282253	SCV000362301	likely benign	Renal hypodysplasia/aplasia 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000337299	SCV000362302	benign	Multiple endocrine neoplasia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Counsyl	RCV000411174	SCV000489771	likely benign	Multiple endocrine neoplasia type 2B	2015-12-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000409372	SCV000489772	likely benign	Multiple endocrine neoplasia type 2A	2015-12-22	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121994	SCV000711344	likely benign	not specified	2016-12-14	criteria provided, single submitter	clinical testing	p.Gly446Arg in exon 7 of RET: This variant is not expected to have clinical sign ificance because it has been identified in 0.8% (87/10400) of African chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs115423919).
GeneDx	RCV000121994	SCV000716910	likely benign	not specified	2017-10-03	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.
Athena Diagnostics	RCV000712293	SCV000842749	benign	not provided	2018-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121994	SCV001338394	benign	not specified	2020-02-26	criteria provided, single submitter	clinical testing	Variant summary: RET c.1336G>C (p.Gly446Arg) results in a non-conservative amino acid change located in the RET cadherin-like domain 4 (IPR041317) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0008 in 282840 control chromosomes, predominantly at a frequency of 0.0083 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 200 fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2 phenotype (3.7e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as benign (4x) / likely benign (4x). Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000162955	SCV002529921	benign	Hereditary cancer-predisposing syndrome	2020-12-18	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000411174	SCV004017350	benign	Multiple endocrine neoplasia type 2B	2023-07-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000712293	SCV004220033	benign	not provided	2018-05-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001083435	SCV004357230	benign	Multiple endocrine neoplasia, type 2	2022-11-17	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000712293	SCV005220643	likely benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000121994	SCV000086205	not provided	not specified	2013-09-19	no assertion provided	reference population