Submissions for variant NM_004360.5(CDH1):c.1746dup (p.Leu583fs)

dbSNP: rs1131690817

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328377	SCV001943333	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-04	reviewed by expert panel	curation	The c.1746dup p.(Leu583fs) 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.
Ambry Genetics	RCV000492101	SCV000580707	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-09	criteria provided, single submitter	clinical testing	The c.1746dupG pathogenic mutation, located in coding exon 12 of the CDH1 gene, results from a duplication of G at nucleotide position 1746, causing a translational frameshift with a predicted alternate stop codon (p.L582Lfs*6). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000657176	SCV000778897	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in CDH1 is denoted c.1746dupG at the cDNA level and p.Leu583AlafsX5 (L583AfsX5) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TTCT[dupG]CTGA. The duplication causes a frameshift which changes a Leucine to an Alanine at codon 583, and creates a premature stop codon at position 5 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. CDH1 c.1746dupG has been identified in at least one individual undergoing multigene cancer panel testing (LaDuca 2017). Based on currently available evidence, we consider this duplication to be pathogenic.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV001712454	SCV003926847	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PVS1; PS4_Supporting; PM2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV001712454	SCV004044618	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-14	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.