Submissions for variant NM_004360.5(CDH1):c.438_439del (p.Pro147fs)

dbSNP: rs1555515197

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328430	SCV001365452	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-04	reviewed by expert panel	curation	The c.438_439delTC p.(Pro147Trpfs*20) 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.
Color Diagnostics, LLC DBA Color Health	RCV000583014	SCV000689538	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-06	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 4 of the CDH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001195168	SCV002216049	pathogenic	Hereditary diffuse gastric adenocarcinoma	2021-04-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with CDH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro147Trpfs*20) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070).
Myriad Genetics, Inc.	RCV001195168	SCV004043757	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.