Submissions for variant NM_004360.5(CDH1):c.454_460del (p.Gln152fs)

dbSNP: rs1131690815

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328452	SCV001142216	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-25	reviewed by expert panel	curation	The c.454_460delCAGAAGA p.(Gln152Glufs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 26182300). 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 (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting.
GeneDx	RCV000657322	SCV000779053	likely pathogenic	not provided	2017-08-07	criteria provided, single submitter	clinical testing	This deletion of seven nucleotides in CDH1 is denoted c.454_460delCAGAAGA at the cDNA level and p.Gln152GlufsX61 (Q152EfsX61) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAGA[delCAGAAGA]GAGA. The deletion causes a frameshift which changes a Glutamine to a Glutamic Acid at codon 152, and creates a premature stop codon at position 61 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.454_460delCAGAAGA, also published as c.447_453delCAGAAGA using alternate nomenclature, has been observed in at least one proband with diffuse gastric cancer and a family history of gastric cancer (Hansford 2015). Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991079	SCV001587261	pathogenic	Hereditary diffuse gastric adenocarcinoma	2020-06-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This variant has been observed in individual(s) with diffuse gastric cancer (PMID: 26182300). This variant is also known as c.447_453delCAGAAGA in the literature. ClinVar contains an entry for this variant (Variation ID: 545785). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln152Glufs*61) in the CDH1 gene. It is expected to result in an absent or disrupted protein product.
Myriad Genetics, Inc.	RCV000991079	SCV004044448	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.
Ambry Genetics	RCV004025998	SCV005022418	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-22	criteria provided, single submitter	clinical testing	The c.454_460delCAGAAGA pathogenic mutation, located in coding exon 4 of the CDH1 gene, results from a deletion of 7 nucleotides at nucleotide positions 454 to 460, causing a translational frameshift with a predicted alternate stop codon (p.Q152Efs*61). This variant has been observed in a study of patients with Hereditary Diffuse Gastric Cancer; this patient had diffuse gastric cancer at age 42 and a family history of gastric cancer and lobular breast cancer (Hansford S et al. JAMA Oncol, 2015 Apr;1:23-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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.