Submissions for variant NM_004360.5(CDH1):c.1460_1461del (p.Val487fs)

dbSNP: rs1567508939

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328455	SCV001142251	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-04	reviewed by expert panel	curation	The c.1460_1461del (p.Val487Alafs*3) 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.
Invitae	RCV000687067	SCV000814618	pathogenic	Hereditary diffuse gastric adenocarcinoma	2018-04-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val487Alafs*3) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDH1-related disease. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001556232	SCV001777773	pathogenic	not provided	2019-06-07	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 in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002388201	SCV002697158	pathogenic	Hereditary cancer-predisposing syndrome	2014-07-23	criteria provided, single submitter	clinical testing	The c.1460_1461delTG pathogenic mutation, located in coding exon 10 of the CDH1 gene, results from a deletion of two nucleotides between positions 1460 and 1461, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).