ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1477G>C (p.Val493Leu)

gnomAD frequency: 0.00003  dbSNP: rs730881666
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160392 SCV000210915 uncertain significance not provided 2023-12-19 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer and no known personal or family history of gastric cancer in a study of CDH1 variants (PMID: 36436516); This variant is associated with the following publications: (PMID: 22722829, 15235021, 22850631, 36436516)
Labcorp Genetics (formerly Invitae), Labcorp RCV000206225 SCV000260134 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-12-07 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 493 of the CDH1 protein (p.Val493Leu). This variant is present in population databases (rs730881666, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 182398). 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 leucine 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 RCV000221777 SCV000273932 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-21 criteria provided, single submitter clinical testing The p.V493L variant (also known as c.1477G>C), located in coding exon 10 of the CDH1 gene, results from a G to C substitution at nucleotide position 1477. The valine at codon 493 is replaced by leucine, 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.
Color Diagnostics, LLC DBA Color Health RCV000221777 SCV000689455 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-19 criteria provided, single submitter clinical testing This missense variant replaces valine with leucine at codon 493 of the CDH1 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 performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 8/251488 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001800470 SCV002046284 uncertain significance not specified 2020-10-16 criteria provided, single submitter clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000206225 SCV003926800 uncertain significance Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing Not applicable criteria (PMID: 30311375)
Baylor Genetics RCV003462088 SCV004215639 uncertain significance Familial cancer of breast 2023-09-24 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000221777 SCV000886678 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 no assertion criteria provided clinical testing

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