ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.687+1G>A

dbSNP: rs1567504977
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 RCV003328457 SCV001142234 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2024-03-25 reviewed by expert panel curation The c.687+1G>A is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in three families meeting IGCLC criteria for HDGC (PS4_Moderate; PMID: 15235021 and 30306390, SCV000815329.1). The variant was also found to co-segregate with HDGC in a family with HDGC and cleft lip/palete (PP1_Supporting; PMID: 30306390). RNA analysis demonstrated an in-frame deletion of 14 amino acids from exon 5, r.646_687del p.(V216_T229del) (PS3_Supporting; PMID: 30306390 and internal laboratory data). In summary, 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_Strong, PS3_Supporting, PM2_Supporting, PS4_Moderate, PM5_Supporting and PP1_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV000687744 SCV000815329 pathogenic Hereditary diffuse gastric adenocarcinoma 2018-02-24 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant has been reported in individuals affected with diffuse gastric cancer who also had a family history of gastric cancer and/or lobular breast cancer (PMID: 15235021, Invitae). This variant is also known as IVS5(+1) G>A in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 5 of the CDH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics RCV001025753 SCV001188003 pathogenic Hereditary cancer-predisposing syndrome 2019-10-28 criteria provided, single submitter clinical testing The c.687+1G>A pathogenic mutation results from a G to A substitution one nucleotide after coding exon 5 of the CDH1 gene. This pathogenic mutation has been detected in two families meeting clinical criteria for hereditary diffuse gastric cancer (Obermair F et al. Fam. Cancer, 2019 04;18:253-260, Brooks-Wilson AR et al. J. Med. Genet., 2004 Jul;41:508-17). RNA analyses have shown that this mutation abolishes the native donor site, resulting in an abnormal transcript with 42 nucleotides deleted from exon 5 (Obermair F et al. Fam. Cancer, 2019 04;18:253-260; Ambry internal data). Another mutation at this position (c.687+1G>C) was reported in a proband with a family history of diffuse gastric cancer (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc. RCV000687744 SCV004045012 likely pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-09 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

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.