Submissions for variant NM_020975.6(RET):c.653C>G (p.Pro218Arg)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002364311	SCV002661249	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-12	criteria provided, single submitter	clinical testing	The p.P218R variant (also known as c.653C>G), located in coding exon 4 of the RET gene, results from a C to G substitution at nucleotide position 653. The proline at codon 218 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in an pediatric individual diagnosed with osteosarcoma (Kovac M et al. J Med Genet, 2021 01;58:20-24). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003103307	SCV002981971	uncertain significance	Multiple endocrine neoplasia, type 2	2023-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 218 of the RET protein (p.Pro218Arg). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with osteoblastic osteosarcoma (PMID: 32179705). ClinVar contains an entry for this variant (Variation ID: 1754100). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
GeneDx	RCV004774670	SCV005385251	uncertain significance	not provided	2024-01-05	criteria provided, single submitter	clinical testing	Observed in an individual with osteosarcoma (PMID: 32179705); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14633923, 32179705)
All of Us Research Program, National Institutes of Health	RCV003103307	SCV005430302	uncertain significance	Multiple endocrine neoplasia, type 2	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 218 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with osteosarcoma (PMID: 32179705). This variant has been identified in 1/31360 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.