Submissions for variant NM_004360.5(CDH1):c.1003C>T (p.Arg335Ter)

gnomAD frequency: 0.00001  dbSNP: rs587780784

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328190	SCV000864589	pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-29	reviewed by expert panel	curation	The c.1003C>T (p.Arg335*) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant was found to co-segregate with disease in multiple affected family members, with >7 meioses observed across at least two families (PP1_Strong; PMID: 16061854, 22723466, 17522512). 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, PP1_Strong, PM5_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123230	SCV000166536	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg335*) 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 present in population databases (rs587780784, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with diffuse gastric cancer (PMID: 11948460, 16061854, 17522512, 18442100, 20719348, 22723466, 26072394). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 136055). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000130670	SCV000185556	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	The p.R335* pathogenic mutation (also known as c.1003C>T), located in coding exon 7 of the CDH1 gene, results from a C to T substitution at nucleotide position 1003. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation has been reported in multiple individuals/ families with hereditary diffuse gastric cancer syndrome (Jonsson BA et al. Int J. Cancer 2002;98:838-843; Suriano G et al. Clin. Can. Res. 2005;11(15):5401-5409; Norton JA et al. Annals of Surgery 2007 Jun;245(6):873-879; Chen Y et al. Ann. Surg. Oncol. 2011 Sep;18:2594-8; Kim S et al. Fam. Cancer 2013 Sep;12(3):503-7; van der Post RS et al. Gastroenterology 2015 Oct;149(4):897-906.e19; Slavin T et al. Cancer Genet. 2017 Oct;216-217:111-119; Ambry internal data). 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.
GeneDx	RCV000218355	SCV000279447	pathogenic	not provided	2018-01-25	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted CDH1 c.1003C>T at the cDNA level and p.Arg335Ter (R335X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple hereditary diffuse gastric cancer families (Jonsson 2002, Suriano 2005, Norton 2007, Onitilo 2011, Kim 2013, van der Post 2015) and is considered pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000130670	SCV001356098	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 7 of the CDH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with hereditary diffuse gastric cancer (PMID: 11948460, 16061854, 17522512, 18442100, 19269290, 20719348, 21424370*, 22723466, 23264079, 26072394, 28688938). It has been shown that this variant co-segregated with hereditary diffuse gastric cancer in multiple unrelated families (PMID: 16061854, 17522512, 22723466). This variant has been identified in 3/282628 chromosomes 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.
Sema4, Sema4	RCV000130670	SCV002531131	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-11	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000218355	SCV002774331	pathogenic	not provided	2021-08-10	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of CDH1 protein synthesis. In addition, it has been described in individuals and/or families with hereditary diffuse gastric cancer (PMID: 31589614 (2019), 31514334 (2019), 29025585 (2017), 26072394 (2015), 22723466 (2013), 21424370 (2011), 20719348 (2011), 20373070 (2010)). Based on the available information, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002492442	SCV002795664	pathogenic	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2022-05-10	criteria provided, single submitter	clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000123230	SCV003926713	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PVS1; PS4; PP1_Strong (PMID: 30311375)
Myriad Genetics, Inc.	RCV000123230	SCV004043108	pathogenic	Hereditary diffuse gastric adenocarcinoma	2023-06-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Pathway Genomics	RCV000123230	SCV000189914	pathogenic	Hereditary diffuse gastric adenocarcinoma	2014-07-24	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162562	SCV002758456	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research