ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1679C>G (p.Thr560Arg) (rs746481984)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492731 SCV000580704 likely pathogenic Hereditary cancer-predisposing syndrome 2016-04-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: in silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification
ClinGen CDH1 Variant Curation Expert Panel RCV000678243 SCV000864620 pathogenic Hereditary diffuse gastric cancer 2018-11-21 reviewed by expert panel curation The c.1679C>G (p.Thr560Arg) variant is absent in the gnomAD cohort (PM2;http://gnomad.broadinstitute.org). There are at least 3 in silico predictors in agreement that this variant affects splicing (PP3). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 27880784). Additionally, the variant was found to co-segregation with disease in multiple affected family members, with >7 meioses observed across at least 4 families (PP1_Strong; PMID: 27880784, 29769627). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 27880784, 29769627, 23709761 and SCV000580704.2). 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: PM2, PP3, PS3, PP1_Strong, PS4.
Familial Cancer Clinical Unit,Spanish National Cancer Research Centre (CNIO) RCV000678243 SCV000693437 pathogenic Hereditary diffuse gastric cancer no assertion criteria provided clinical testing
GeneDx RCV000219965 SCV000279476 uncertain significance not specified 2015-10-14 criteria provided, single submitter clinical testing This variant was observed in at least one individual diagnosed with early-onset diffuse gastric cancer (Benusiglio 2013). CDH1 Thr560Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. CDH1 Thr560Arg occurs at a position that is conserved in mammals and is located in the Cadherin 4 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether CDH1 Thr560Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000678243 SCV000815215 pathogenic Hereditary diffuse gastric cancer 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 560 of the CDH1 protein (p.Thr560Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with diffuse gastric cancer in several families (PMID: 27880784, 29769627). Additionally, this variant has been reported in an individual with early-onset diffuse gastric cancer (PMID: 23709761). ClinVar contains an entry for this variant (Variation ID: 234554). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change creates a cryptic donor splice site, giving rise to an aberrant transcript and a truncated CDH1 protein (PMID: 27880784, 29769627). For these reasons, this variant has been 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.