Submissions for variant NM_004360.5(CDH1):c.2245C>T (p.Arg749Trp)

dbSNP: rs776975632

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328355	SCV000864626	uncertain significance	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-28	reviewed by expert panel	curation	The NM_004360.5(CDH1):c.2245C>T (p.Arg749Trp) variant is a missense variant in exon 14 and results in the change of an Arginine to a Tryptophan. This variant is present in <1/100,000 alleles in the ExAC and gnomAD cohort (PM2_Supporting). Furthermore, it has been observed in > 10 individuals (34) without DGC, SRC tumours or LBC and whose families do not suggest HDGC. This variant has been reported in four families meeting HDGC clinical criteria, however, this represents only 11% of all families carrying this variant (threshold is 30% to consider applying PS4). Given that multiple families with this variants meet the HDGC criteria, CDH1-VCEP recommended not to apply BS2 code. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting.
GeneDx	RCV000479819	SCV000566200	uncertain significance	not provided	2018-04-25	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.2245C>T at the cDNA level, p.Arg749Trp (R749W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been suggested in several in vitro based assays to result in reduced E-cadherin surface expression and cell-cell adhesion, as well as increased cell motility and invasion compared to wild type controls (Kaurah 2007, Simoes-Correia 2008, Mateus 2009, Figueiredo 2013). While CDH1 Arg749Trp has also been observed in a family with three cases of gastric cancer, two of which are reported as diffuse gastric cancer, segregation analysis was not completed (Kaurah 2007). CDH1 Arg749Trp was not observed in large population cohorts. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Arg749Trp is located in the cytoplasmic domain and Hakai p120-catenin binding regions (Figueiredo 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. While there are in vitro functional assays suggesting pathogenicity, internal observations at this laboratory and other clinical laboratories are not suggestive of hereditary diffuse gastric cancer. Based on currently available evidence, it is unclear whether CDH1 Arg749Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl	RCV000663000	SCV000786002	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2018-02-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479819	SCV000888034	uncertain significance	not provided	2018-05-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000774774	SCV000908759	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 749 of the CDH1 protein. Functional studies have shown the mutant protein to be defective in cell surface expression, cell adhesion, motility and cell invasion ability (PMID 17545690, 18772194, 19268661, 22850631). The severity of the defect differs broadly. This variant has been reported in a family with five individuals affected with gastric cancer (ages 36-49), two of whom with diffuse cancer, but each individual's genotype was not provided (PMID: 17545690). This variant has been observed in an individual affected with breast cancer (PMID: 30653559). This variant has been identified in 1/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000774774	SCV001175683	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-16	criteria provided, single submitter	clinical testing	The p.R749W variant (also known as c.2245C>T), located in coding exon 14 of the CDH1 gene, results from a C to T substitution at nucleotide position 2245. The arginine at codon 749 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration, located in the intracellular juxtamembrane domain of the CDH1 gene, has been reported in 1 of 38 families diagnosed clinically with hereditary diffuse gastric cancer (HDGC) who were analyzed for CDH1 mutations, however segregation analysis was not completed in this family (Kaurah P et al. JAMA, 2007 Jun;297:2360-72). Several in vitro based studies showed that this variant increased cell motility and invasion compared to wild type controls as well as reduced expression and interaction with E-cadherin (Figueiredo J et al. Eur. J. Hum. Genet., 2013 Mar;21:301-9; Sanches JM et al. Eur. J. Hum. Genet., 2015 Aug;23:1072-9; Mateus AR et al. Exp. Cell Res., 2009 May;315:1393-402; Mestre T et al. Sci Rep, 2016 05;6:25101). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000663000	SCV001204783	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 749 of the CDH1 protein (p.Arg749Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with diffuse gastric cancer (PMID: 17545690). ClinVar contains an entry for this variant (Variation ID: 418841). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDH1 function (PMID: 17545690, 18772194, 19268661, 22850631, 25388006, 34486077). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV000479819	SCV002503292	uncertain significance	not provided	2020-05-08	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000663000	SCV002523186	likely pathogenic	Hereditary diffuse gastric adenocarcinoma	2020-07-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004568154	SCV005060126	uncertain significance	Familial cancer of breast	2023-12-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355065	SCV001549831	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Arg749Trp variant was identified in 1 of 76 proband chromosomes (frequency: 0.013) from individuals or families with Diffuse Gastric Cancer, the family included 2 cases of diffuse gastric cancer and one case of breast cancer however segregation analysis was not reported (Kaurah 2007). The variant was also identified in dbSNP (ID: rs776975632) as With Uncertain significance allele, in ClinVar and Clinvitae (classified as uncertain significance by GeneDx), Insight Colon Cancer Gene Variant Database, and the Zhejiang Colon Cancer database. GeneDx reports that the variant was observed in patients with phenotypes that are not suggestive of Hereditary Diffuse Gastric Cancer (ClinVar). The variant was not identified in the Cosmic or MutDB, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. Several in vitro functional studies were identified on this variant that suggests that the variant is pathogenic. Multiple studies have displayed that the variant reduces the level of E-cadherin found at the cell membrane and retained the protein in the endoplasmic reticulum (Simoes-Correia 2008, Mateus 2009, Figueiredo 2013, Sanches 2015). One study displayed that the variant produces low total and surface E-cadherin expression, despite the normal RNA levels, because the variant reduces binding of E-cadherin to B-catenin increasing the likelihood of degradation due to ubiquitination (Figueiredo 2013). Kaurah et al. (2007) expressed the c.2245C>T variant in CHO cells and displayed that the variant failed to cause cell aggregation that the wildtype E-cadherin causes and the variant increased the invasion of E-cadherin into collagen matrices at significantly higher rates than wildtype. Additional groups have also displayed increased cell motility due to the c.2245C>T variant (Mateus 2009, Mestre 2016). The p.Arg749 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.