Submissions for variant NM_004360.5(CDH1):c.2276del (p.Gly759fs)

dbSNP: rs1555517680

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328450	SCV001142219	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-25	reviewed by expert panel	curation	The c.2276delG (p.Gly759Glufs) 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 16061854). In summary, 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	RCV000657197	SCV000778923	pathogenic	not provided	2018-04-27	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in CDH1 is denoted c.2276delG at the cDNA level and p.Gly759GlufsX11 (G759EfsX11) at the protein level. The normal sequence, with the base that is deleted in brackets, is GAAG[delG]AGGC. The deletion causes a frameshift which changes a Glycine to a Glutamic Acid at codon 759, and creates a premature stop codon at position 11 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.2276delG has been observed in at least one family with confirmed diffuse gastric and lobular breast cancer (Suriano 2005). We consider this variant to be pathogenic.
Ambry Genetics	RCV001014872	SCV001175637	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-06	criteria provided, single submitter	clinical testing	The c.2276delG pathogenic mutation, located in coding exon 14 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 2276, causing a translational frameshift with a predicted alternate stop codon (p.G759Efs*11). This mutation has been previously reported in a family with diffuse gastric cancer and lobular breast cancer (Suriano G et al. Clin. Cancer Res. 2005 Aug;11:5401-9). 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.
Myriad Genetics, Inc.	RCV003336120	SCV004043542	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.