Submissions for variant NM_020975.6(RET):c.602G>C (p.Ser201Thr)

gnomAD frequency: 0.00001  dbSNP: rs898525501

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000679753	SCV000807057	uncertain significance	not provided	2017-07-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001066218	SCV001231223	uncertain significance	Multiple endocrine neoplasia, type 2	2024-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 201 of the RET protein (p.Ser201Thr). This variant is present in population databases (no rsID available, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 560871). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002352100	SCV002660451	likely benign	Hereditary cancer-predisposing syndrome	2023-12-18	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.
Fulgent Genetics, Fulgent Genetics	RCV002499197	SCV002805612	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2021-10-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003459652	SCV004208689	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-09-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001066218	SCV004827907	uncertain significance	Multiple endocrine neoplasia, type 2	2024-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 201 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related disorders in the literature. This variant has been identified in 1/31394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV000679753	SCV005080952	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14633923)