Submissions for variant NM_004360.5(CDH1):c.382del (p.His128fs)

dbSNP: rs1555514492

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328424	SCV000864604	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-29	reviewed by expert panel	curation	The c.382delC (p.His128Ilefs*87) 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: 15235021). 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.
Ambry Genetics	RCV000571499	SCV000675986	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	clinical testing	The c.382delC pathogenic mutation, located in coding exon 3 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 382, causing a translational frameshift with a predicted alternate stop codon (p.H128Ifs*87). This mutation has been identified in multiple individuals with gastric cancer and a family history of HDGC (Brooks-Wilson AR. J. Med. Genet. 2004 Jul; 41(7):508-17; Oliveira C. Gastroenterology. 2009 Jun; 136(7):2137-48). 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.
Counsyl	RCV000576815	SCV000677781	pathogenic	Hereditary diffuse gastric adenocarcinoma	2017-01-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000576815	SCV000760844	pathogenic	Hereditary diffuse gastric adenocarcinoma	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His128Ilefs*87) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with diffuse gastric cancer (PMID: 15235021, 19269290, 26182300). ClinVar contains an entry for this variant (Variation ID: 486824). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000576815	SCV000919108	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-12-01	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.382delC (p.His128IlefsX87) results in a premature termination codon and is expected to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 250542 control chromosomes (gnomAD). c.382delC has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer (e.g. Brooks-Wilson_2004, Oliveira_2009, Hansford_2015). These data indicate that the variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15235021, 26182300, 20233471). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002483545	SCV002793394	pathogenic	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2021-12-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000576815	SCV004019576	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-03-03	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	RCV003471911	SCV004210571	pathogenic	Familial cancer of breast	2021-11-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000571499	SCV004360444	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-19	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 3 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. This variant has been reported in multiple individuals affected with diffuse gastric cancer in the literature (PMID: 15235021, 19269290, 26182300). 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.