ClinVar Miner

Submissions for variant NM_020975.6(RET):c.733G>A (p.Val245Met)

dbSNP: rs1837733068
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001056109 SCV001220530 uncertain significance Multiple endocrine neoplasia, type 2 2023-12-31 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 245 of the RET protein (p.Val245Met). This variant is not present in population databases (gnomAD no frequency). 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: 851671). 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 methionine 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.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University RCV003153912 SCV003843727 benign Ovarian cancer 2022-01-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV003160453 SCV003911398 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-31 criteria provided, single submitter clinical testing The p.V245M variant (also known as c.733G>A), located in coding exon 4 of the RET gene, results from a G to A substitution at nucleotide position 733. The valine at codon 245 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is 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 RCV001056109 SCV004828808 uncertain significance Multiple endocrine neoplasia, type 2 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 245 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 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.

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