Submissions for variant NM_020975.6(RET):c.224C>T (p.Thr75Met)

gnomAD frequency: 0.00006  dbSNP: rs142641173

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690605	SCV000818300	uncertain significance	Multiple endocrine neoplasia, type 2	2024-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 75 of the RET protein (p.Thr75Met). This variant is present in population databases (rs142641173, gnomAD 0.01%). 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: 569870). 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	RCV001014923	SCV001175696	likely benign	Hereditary cancer-predisposing syndrome	2023-07-10	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	RCV001662755	SCV001875324	uncertain significance	not provided	2021-07-15	criteria provided, single submitter	clinical testing	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: 27535533)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001662755	SCV002011453	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153803	SCV003843858	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001662755	SCV005623083	uncertain significance	not provided	2024-06-05	criteria provided, single submitter	clinical testing