Submissions for variant NM_020975.6(RET):c.3112A>G (p.Thr1038Ala)

gnomAD frequency: 0.00047  dbSNP: rs201740483

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083486	SCV000166624	likely benign	Multiple endocrine neoplasia, type 2	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163463	SCV000214014	likely benign	Hereditary cancer-predisposing syndrome	2019-01-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000679744	SCV000713989	likely benign	not provided	2021-03-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24336963, 28873162, 24429398)
Counsyl	RCV000663277	SCV000786514	likely benign	Multiple endocrine neoplasia type 2A	2018-05-16	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761007	SCV000890922	uncertain significance	Ewing sarcoma of soft tissue	2016-03-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000663277	SCV001138037	likely benign	Multiple endocrine neoplasia type 2A	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001106024	SCV001263048	likely benign	Pheochromocytoma	2018-05-22	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	RCV001106025	SCV001263049	benign	Renal hypodysplasia/aplasia 1	2018-05-22	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001108238	SCV001265452	benign	Hirschsprung disease, susceptibility to, 1	2018-05-22	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001108239	SCV001265453	benign	Multiple endocrine neoplasia	2018-05-22	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001818296	SCV001469971	benign	not specified	2022-10-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene.
Athena Diagnostics	RCV000679744	SCV001476551	likely benign	not provided	2019-10-25	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000679744	SCV002011446	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818296	SCV002066607	likely benign	not specified	2020-01-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163463	SCV002527899	likely benign	Hereditary cancer-predisposing syndrome	2021-06-13	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818296	SCV002550395	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818296	SCV002766427	likely benign	not specified	2022-11-04	criteria provided, single submitter	clinical testing	Variant summary: RET c.3112A>G (p.Thr1038Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 251466 control chromosomes, predominantly within the Finnish- and Non-Finnish European subpopulations, at a frequency of about 0.0019 and 0.001, respectively (gnomAD). The observed variant frequencies in these subpopulations are approximately 25-50 fold higher than the estimated maximal expected allele frequency (MPAF) for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2 phenotype (3.7e-05), suggesting that the variant is a benign polymorphism. The variant, c.3112A>G, has been reported in the literature in multigene panel testing studies in individuals affected with various tumor phenotypes, mostly outside the RET gene associated tumor spectrum, and without strong evidence for causality (e.g. Zhang_2015, Kim_2018, Zhunussova_2019, Henn_2019, Backman_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Multiple Endocrine Neoplasia Type 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seventeen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, classifying the variant as likely benign (n=12), VUS (n=4), or benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV001083486	SCV004357255	likely benign	Multiple endocrine neoplasia, type 2	2022-06-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528841	SCV000807046	likely benign	RET-related disorder	2022-12-15	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000679744	SCV001743249	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000679744	SCV001807685	likely benign	not provided		no assertion criteria provided	clinical testing