Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003328437 | SCV001437631 | likely pathogenic | CDH1-related diffuse gastric and lobular breast cancer syndrome | 2023-08-30 | reviewed by expert panel | curation | The c.2446A>T (p.Lys816Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein within the NMD-resistant zone and located upstream the most 3' well-characterized pathogenic variant c.2506G>T (p.Glu836Ter) (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). The variant has been reported in one family meeting clinical criteria for HDGC (PS4_Supporting; PMID: 29798843). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel(Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4_Supporting. |
| Ambry Genetics | RCV000593954 | SCV000700320 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-02-02 | criteria provided, single submitter | clinical testing | The p.K816* variant (also known as c.2446A>T), located in coding exon 16 of the CDH1 gene, results from an A to T substitution at nucleotide position 2446. This changes the amino acid from a lysine to a stop codon within coding exon 16. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of CDH1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 67 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, the deleted region eliminates the catenin-binding domain, which is important for regulating the stability of cadherin mediated cell-cell adhesion (Ishiyama N et al. Cell. 2010 Apr;141:117-28). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV000639208 | SCV000760778 | likely pathogenic | Hereditary diffuse gastric adenocarcinoma | 2017-12-20 | criteria provided, single submitter | clinical testing | This sequence change results in a premature translational stop signal in the CDH1 gene (p.Lys816*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 67 amino acids of the CDH1 protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is expected to delete the C-terminal portion of the cytoplasmic domain of the CDH1 (E-cadherin) protein, which includes the binding domains for the PIP5K1C (phosphatidylinositol phosphate kinase, type I gamma) and CTNNB1 (beta-catenin) proteins (PMID: 22850631). Loss of these domains is expected to disrupt normal E-cadherin function (PMID: 17261850, 10037790). This suggests that deletion of this region of the CDH1 protein is causative of disease. This variant has not been reported in the literature in individuals with CDH1-related disease. This variant is not present in population databases (ExAC no frequency). |
| Baylor Genetics | RCV003471949 | SCV004210567 | likely pathogenic | Familial cancer of breast | 2022-05-14 | criteria provided, single submitter | clinical testing |