Submissions for variant NM_020975.6(RET):c.1295C>T (p.Ala432Val)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002380630	SCV002690930	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-12	criteria provided, single submitter	clinical testing	The p.A432V variant (also known as c.1295C>T), located in coding exon 7 of the RET gene, results from a C to T substitution at nucleotide position 1295. The alanine at codon 432 is replaced by valine, an amino acid with similar properties. This amino acid position is not well 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003444270	SCV004171434	uncertain significance	Multiple endocrine neoplasia type 2A	2023-11-28	criteria provided, single submitter	clinical testing	The RET c.1295C>T (p.Ala432Val) missense change has a maximum subpopulation frequency of 0.008% 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.
All of Us Research Program, National Institutes of Health	RCV004007298	SCV004833066	uncertain significance	Multiple endocrine neoplasia, type 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 432 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 disorders in the literature. This variant has been identified in 5/282564 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	RCV004572400	SCV005054227	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-11-29	criteria provided, single submitter	clinical testing
GeneDx	RCV004725265	SCV005331649	uncertain significance	not provided	2024-02-16	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)