Submissions for variant NM_020975.6(RET):c.973G>A (p.Ala325Thr)

gnomAD frequency: 0.00002  dbSNP: rs779719517

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528670	SCV000658505	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 325 of the RET protein (p.Ala325Thr). This variant is present in population databases (rs779719517, gnomAD 0.005%). 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: 477393). 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 threonine 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.
Ambry Genetics	RCV000566312	SCV000674818	likely benign	Hereditary cancer-predisposing syndrome	2018-10-10	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.
Mendelics	RCV000709105	SCV000838374	uncertain significance	Multiple endocrine neoplasia type 2A	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV003327423	SCV004034696	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14633923, 30857943, 35739278, 35264596)
Baylor Genetics	RCV003459267	SCV004208710	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-08-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000528670	SCV004357224	uncertain significance	Multiple endocrine neoplasia, type 2	2023-04-21	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 325 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 6/248794 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.
All of Us Research Program, National Institutes of Health	RCV000528670	SCV004838629	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 325 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 6/248794 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.