Submissions for variant NM_020975.6(RET):c.2906G>A (p.Arg969Gln)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002761246	SCV003019203	uncertain significance	Multiple endocrine neoplasia, type 2	2022-07-29	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with RET-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 969 of the RET protein (p.Arg969Gln).
All of Us Research Program, National Institutes of Health	RCV002761246	SCV004838700	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 969 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Ambry Genetics	RCV004067944	SCV005028279	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-10	criteria provided, single submitter	clinical testing	The p.R969Q variant (also known as c.2906G>A), located in coding exon 17 of the RET gene, results from a G to A substitution at nucleotide position 2906. The arginine at codon 969 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.