Submissions for variant NM_004360.5(CDH1):c.455_465del (p.Gln152fs)

dbSNP: rs1555515210

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328431	SCV001365424	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-04	reviewed by expert panel	curation	The c.455_465delAGAAGAGAGAC p.(Gln152Leufs) 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	RCV000584690	SCV000689539	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-17	criteria provided, single submitter	clinical testing	This variant deletes 11 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. To our knowledge, 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.
GeneDx	RCV000657353	SCV000779085	likely pathogenic	not provided	2017-07-10	criteria provided, single submitter	clinical testing	This deletion of 11 nucleotides in CDH1 is denoted c.455_465del11 at the cDNA level and p.Gln152LeufsX12 (Q152LfsX12) at the protein level. The surrounding sequence is AGAC[del11]TGGG. The deletion causes a frameshift which changes a Glutamine to a Leucine at codon 152, and creates a premature stop codon at position 12 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Myriad Genetics, Inc.	RCV003336073	SCV004044458	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.