Submissions for variant NM_004360.5(CDH1):c.2386dup (p.Arg796fs)

dbSNP: rs1375617541

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328151	SCV001142262	likely pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-29	reviewed by expert panel	curation	The c.2265T>A p.(Arg796Profs*11) variant is predicted to result in a premature stop codon that leads to a truncated protein (disrupting the last 87 amino acid residues of the CDH1 protein), and is located within the nonsense-mediated decay resistance region (downstream of aa 795) upstream of c.2506G>T p.(Glu836*) variant (PVS1_strong). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 9537325). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). In summary, this variant meets criteria to be classified as likely 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, PM2_Supporting, PS4_Supporting.
Invitae	RCV000013023	SCV001382869	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg796Profs*11) in the CDH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 87 amino acid(s) of the CDH1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with lobular breast cancer and diffuse gastric cancer (PMID: 9537325, 23709761, 29589180). This variant is also known as c.2381_2386insC. ClinVar contains an entry for this variant (Variation ID: 12236). This variant disrupts a region of the CDH1 protein in which other variant(s) (p.Phe810Leufs*6) have been determined to be pathogenic (PMID: 26182300; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001804726	SCV002052410	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-12	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 15 of the CDH1 gene, creating a frameshift and premature translation stop signal. This variant truncates the last 87 amino acid residues of the CDH1 protein and is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with diffuse gastric cancer and lobular breast cancer in the literature (PMID: 9537325, 23709761, 29589180). 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.
Ambry Genetics	RCV001804726	SCV002737067	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-12	criteria provided, single submitter	clinical testing	The c.2386dupC pathogenic mutation, located in coding exon 15 of the CDH1 gene, results from a duplication of C at nucleotide position 2386, causing a translational frameshift with a predicted alternate stop codon (p.R796Pfs*11). This alteration has been identified a family affected with diffuse gastric cancer (Guilford P et al. Nature, 1998 Mar;392:402-5). This alteration occurs at the 3' terminus of CDH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 87 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV000013023	SCV004044437	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-15	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003460462	SCV004215661	pathogenic	Familial cancer of breast	2023-08-21	criteria provided, single submitter	clinical testing
OMIM	RCV000013023	SCV000033268	pathogenic	Hereditary diffuse gastric adenocarcinoma	1998-03-26	no assertion criteria provided	literature only