Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000217435 | SCV000279467 | uncertain significance | not provided | 2016-04-04 | criteria provided, single submitter | clinical testing | This variant is denoted CDH1 c.1336G>A at the cDNA level, p.Ala446Thr (A446T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. CDH1 Ala446Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Ala446Thr occurs at a position that is not conserved and is located in the Cadherin 3 domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether CDH1 Ala446Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Labcorp Genetics |
RCV000534484 | SCV000637716 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2022-11-17 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 234548). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 446 of the CDH1 protein (p.Ala446Thr). |
| Ambry Genetics | RCV001010832 | SCV001171084 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-05-17 | criteria provided, single submitter | clinical testing | The p.A446T variant (also known as c.1336G>A), located in coding exon 10 of the CDH1 gene, results from a G to A substitution at nucleotide position 1336. The alanine at codon 446 is replaced by threonine, an amino acid with similar properties. This variant was reported in 1/53,461 controls and was not observed in 60,466 breast cancer cases (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other 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, |
RCV001010832 | SCV001350259 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-03-23 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with threonine at codon 446 of the CDH1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. 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 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. |
| Center for Genomic Medicine, |
RCV002267972 | SCV002551773 | uncertain significance | not specified | 2024-07-31 | criteria provided, single submitter | clinical testing |