Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000132103 | SCV000187168 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-20 | criteria provided, single submitter | clinical testing | The p.T118R variant (also known as c.353C>G), located in coding exon 3 of the CDH1 gene, results from a C to G substitution at nucleotide position 353. The threonine at codon 118 is replaced by arginine, an amino acid with similar properties. This alteration has been identified in an individual with personal history of diffuse gastric cancer and family history of gastric cancer, type unspecified (Suriano G, et al. J. Mol. Med. 2006 Dec; 84(12):1023-31). Functional studies have shown that p.T118R mutants display an increase in cell migration and invasion potential due to reduced cell to cell adhesion, a known function of E-cadherin (Suriano G, et al. J. Mol. Med. 2006 Dec; 84(12):1023-31. More H, et al. Hum. Mutat. 2007 Feb; 28(2):203). Another study has demonstrated decreased stability of the EGFR/E-cadherin heteromers, resulting in increased EGRF activity (Mateus AR, et al. Exp. Cell Res. 2009 May; 315(8):1393-402). This amino acid position is poorly 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 |
RCV002512549 | SCV003443609 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2023-10-18 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 118 of the CDH1 protein (p.Thr118Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with diffuse gastric cancer (PMID: 17221870). ClinVar contains an entry for this variant (Variation ID: 142730). 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 arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDH1 function (PMID: 17221870, 19268661). 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. |