ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2491G>A (p.Gly831Ser)

gnomAD frequency: 0.00001  dbSNP: rs775981129
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000800320 SCV000940027 uncertain significance Multiple endocrine neoplasia, type 2 2024-12-02 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 831 of the RET protein (p.Gly831Ser). This variant is present in population databases (rs775981129, gnomAD 0.003%). 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: 646100). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine 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 RCV001015690 SCV001176552 uncertain significance Hereditary cancer-predisposing syndrome 2024-11-28 criteria provided, single submitter clinical testing The p.G831S variant (also known as c.2491G>A), located in coding exon 14 of the RET gene, results from a G to A substitution at nucleotide position 2491. The glycine at codon 831 is replaced by serine, 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.
All of Us Research Program, National Institutes of Health RCV000800320 SCV004838677 uncertain significance Multiple endocrine neoplasia, type 2 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces glycine with serine at codon 831 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 1/248734 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.

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