Submissions for variant NM_020975.6(RET):c.143C>T (p.Thr48Met)

dbSNP: rs1427186016

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001011585	SCV001171923	likely benign	Hereditary cancer-predisposing syndrome	2017-11-03	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069718	SCV001234908	uncertain significance	Multiple endocrine neoplasia, type 2	2023-10-04	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 48 of the RET protein (p.Thr48Met). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 819219). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Genetics and Molecular Pathology, SA Pathology	RCV003447573	SCV004175491	uncertain significance	Multiple endocrine neoplasia type 2A	2022-04-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001069718	SCV004828236	uncertain significance	Multiple endocrine neoplasia, type 2	2023-12-10	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 48 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 as a germline variant in individuals affected with RET-related cancer in the literature. This variant has been identified in 1/250216 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	RCV004783877	SCV005396069	uncertain significance	not provided	2024-05-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individual(s) evaluated by whole genome sequencing with no specific phenotype information provided (PMID: 36936415); This variant is associated with the following publications: (PMID: 36936415, 14633923)