Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003328382 | SCV001943349 | likely pathogenic | CDH1-related diffuse gastric and lobular breast cancer syndrome | 2023-08-30 | reviewed by expert panel | curation | The c.2490dupG (p.Leu831AlafsTer4) variant results in a premature stop codon that leads to a truncated protein. It is located within the nonsense mediated decay resistant zone, and upstream of codon 836 where the most 3' pathogenic variant in CDH1 terminates (PVS1_Strong, PMID: 29798843). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in a family meeting HDGC criteria (PS4_Supporting; SCV000580713.3). In summary, the clinical significance of this variant is 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, Supporting, PM2_Supporting |
Ambry Genetics | RCV000492088 | SCV000580713 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2015-07-31 | criteria provided, single submitter | clinical testing | The c.2490dupG variant, located in coding exon 16 of the CDH1 gene, results from a duplication of G at nucleotide position 2490, and causes a translational frameshift with a predicted alternate stop codon (p.L831Afs*4). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of CDH1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 52 amino acids of the protein. The exact functional impact of these altered 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(1):117-28). In addition, this alteration was previously seen in a patient diagnosed with diffuse gastric cancer at 31 (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Invitae | RCV001712455 | SCV003461741 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2022-03-01 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CDH1 protein in which other variant(s) (p.Glu836*) have been determined to be pathogenic (PMID: 29798843). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 428634). This premature translational stop signal has been observed in individuals with diffuse gastric cancer (PMID: 29798843; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu831Alafs*4) in the CDH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acid(s) of the CDH1 protein. |