ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2T>C (p.Met1Thr)

dbSNP: rs1555509623
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328425 SCV001943356 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-25 reviewed by expert panel curation The c.2T>C (p.Met1Thr) variant alters the start codon of the CDH1 coding sequence and is predicted to lead to an absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 2 probands/families meeting HDGC clinical criteria (PS4_moderate; PMID: 20373070, SCV000760804.3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP Variant Interpretation Guidelines Version 3.1 as specified by the CDH1 Variant Curation Expert Panel: PVS1, PS4_moderate, PM2_supporting.
Ambry Genetics RCV000566678 SCV000675988 pathogenic Hereditary cancer-predisposing syndrome 2021-01-12 criteria provided, single submitter clinical testing The p.M1? pathogenic mutation (also known as c.2T>C), located in coding exon 1 of the CDH1 gene, results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This mutation was reported in the literature in a family with hereditary diffuse gastric cancer (Guilford P, Gastric Cancer 2010 Mar; 13(1):1-10). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV000639234 SCV000760804 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Other variant(s) that result in disruption of the initiator methionine (p.Met1) have been determined to be pathogenic (PMID: 16061854, 20373070, 28202063; Invitae). This suggests that this variant may also be clinically significant and likely to be disease-causing. This sequence change affects the initiator methionine of the CDH1 mRNA. The next in-frame methionine is located at codon 246. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with a personal or family history of diffuse gastric cancer and/or lobular breast cancer (PMID: 16061854, 20373070, 28202063; Invitae). ClinVar contains an entry for this variant (Variation ID: 486826). Functional studies for this variant have not been reported. However, translation rescue by the downstream methionine at codon 246 would delete most of the first extracellular cadherin (EC1) domain (amino acid residues 155-262). This domain is important for the formation of intermolecular interactions with other CDH1 molecules to establish cell-cell junctions (PMID: 18726070, 2317870, 20066110).
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001310106 SCV001499639 pathogenic Familial cancer of breast 2020-04-02 criteria provided, single submitter clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000639234 SCV003927039 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PVS1; PS4_Moderate; PM2 (PMID: 30311375)
Myriad Genetics, Inc. RCV000639234 SCV004045138 likely pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-08 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation.

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.