Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003328426 | SCV001437604 | pathogenic | CDH1-related diffuse gastric and lobular breast cancer syndrome | 2023-08-25 | reviewed by expert panel | curation | The c.656del p.(Pro219fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; SCV000760825.3). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. |
Gene |
RCV000578321 | SCV000680444 | likely pathogenic | Hereditary diffuse gastric adenocarcinoma | 2017-09-07 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000578321 | SCV000760825 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2019-05-22 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro219Leufs*31) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 488647). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000759015 | SCV000888037 | likely pathogenic | not provided | 2018-03-01 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV001002307 | SCV001160199 | pathogenic | not specified | 2019-01-14 | criteria provided, single submitter | clinical testing | The CDH1 c.656delC; p.Pro219fs variant, to our knowledge, is not reported in the medical literature but is reported as likely pathogenic/pathogenic in ClinVar (Variation ID: 488647). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Loss-of-function CDH1 variants are considered to be pathogenic (Brooks-Wilson 2004, Guilford 1999). Based on available information, the c.656delC variant is considered to be pathogenic. REFERENCES Brooks-Wilson AR et al. Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Genet. 2004 Jul;41(7):508-17. Guilford PJ et al. E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer. Hum Mutat. 1999;14(3):249-55. |
Myriad Genetics, |
RCV000578321 | SCV004045304 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2023-06-09 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
Gene |
RCV000759015 | SCV005331899 | likely pathogenic | not provided | 2023-08-09 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in a patient with personal and family history of gastric cancer in the literature (Adib et al., 2022); This variant is associated with the following publications: (PMID: 34949788) |