ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.12G>A (p.Trp4Ter)

dbSNP: rs1555509636
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328454 SCV001142267 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-04 reviewed by expert panel curation The c.12G>A (p.Trp4Ter) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). 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 (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting.
Counsyl RCV000662736 SCV000785509 likely pathogenic Hereditary diffuse gastric adenocarcinoma 2017-08-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV002386135 SCV002692474 pathogenic Hereditary cancer-predisposing syndrome 2020-07-20 criteria provided, single submitter clinical testing The p.W4* variant (also known as c.12G>A), located in coding exon 1 of the CDH1 gene, results from a G to A substitution at nucleotide position 12. This changes the amino acid from a tryptophan to a stop codon within coding exon 1. This alteration was identified in an individual at risk for hereditary cancer referred for multigene panel testing (Schroeder C et al. Breast Cancer Res. Treat. 2015 Jul;152(1):129-136). The predicted stop codon for this alteration occurs within the first 150 nucleotides of the CDH1 gene. Therefore, this alteration may escape nonsense-mediated mRNA decay and/or be rescued by reinitiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). However, the impacted region is critical for protein function (van Roy F et al. Cell. Mol. Life Sci. 2008 Nov;65(23):3756-88; Shapiro L et al. Cold Spring Harb Perspect Biol 2009 Sep;1(3):a003053; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health RCV002386135 SCV004360420 pathogenic Hereditary cancer-predisposing syndrome 2023-05-09 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 1 of the CDH1 gene, creating a premature translation stop signal. This variant is expected to disrupt the signal sequence of the protein and result in an absent or non-functional protein product. To our knowledge, this variant has been reported in an individual with a high-risk family profile indicative for hereditary breast and ovarian cancer (PMID: 26022348). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.