Submissions for variant NM_020975.6(RET):c.1493C>T (p.Ala498Val)

gnomAD frequency: 0.00001  dbSNP: rs375677628

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000569143	SCV000674796	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-19	criteria provided, single submitter	clinical testing	The p.A498V variant (also known as c.1493C>T), located in coding exon 7 of the RET gene, results from a C to T substitution at nucleotide position 1493. The alanine at codon 498 is replaced by valine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000696079	SCV000824626	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 498 of the RET protein (p.Ala498Val). This variant is present in population databases (rs375677628, gnomAD 0.002%). 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: 486306). 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 valine 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.
Fulgent Genetics, Fulgent Genetics	RCV002476248	SCV002784332	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2022-05-14	criteria provided, single submitter	clinical testing
GeneDx	RCV002508232	SCV002817885	uncertain significance	not provided	2024-08-07	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14633923)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325206	SCV004031177	uncertain significance	Multiple endocrine neoplasia type 2A	2023-05-31	criteria provided, single submitter	clinical testing	The RET c.1493C>T (p.Ala498Val) missense change has a maximum subpopulation frequency of 0.0017% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type II. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000696079	SCV004357232	uncertain significance	Multiple endocrine neoplasia, type 2	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 498 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 hereditary cancer in the literature. This variant has been identified in 2/249816 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	RCV000696079	SCV004831386	uncertain significance	Multiple endocrine neoplasia, type 2	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 498 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 hereditary cancer in the literature. This variant has been identified in 2/249816 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.
Baylor Genetics	RCV004569286	SCV005054230	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-11-27	criteria provided, single submitter	clinical testing