Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000216294 | SCV000278708 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-17 | criteria provided, single submitter | clinical testing | The p.D569E variant (also known as c.1707C>A), located in coding exon 11 of the CDH1 gene, results from a C to A substitution at nucleotide position 1707. The aspartic acid at codon 569 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Gene |
RCV000479771 | SCV000572231 | uncertain significance | not provided | 2016-11-03 | criteria provided, single submitter | clinical testing | This variant is denoted CDH1 c.1707C>A at the cDNA level, p.Asp569Glu (D569E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAA). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in a head and neck tumor (Zhao 2015). CDH1 Asp569Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. CDH1 Asp569Glu occurs at a position that is conserved across species and is located in the Cadherin 4 Extracellular domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether CDH1 Asp569Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Color Diagnostics, |
RCV000216294 | SCV000905502 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-11-03 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with glutamic acid at codon 569 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251478 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. |
| Labcorp Genetics |
RCV001059355 | SCV001223979 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2023-06-20 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 569 of the CDH1 protein (p.Asp569Glu). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 234181). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). |
| Baylor Genetics | RCV003463601 | SCV004215675 | uncertain significance | Familial cancer of breast | 2023-12-05 | criteria provided, single submitter | clinical testing |