Submissions for variant NM_004360.5(CDH1):c.1225T>C (p.Trp409Arg)

gnomAD frequency: 0.00003  dbSNP: rs587778176

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328189	SCV000864607	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The c.1225T>C (p. Trp409Arg) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
GeneDx	RCV000588122	SCV000210910	uncertain significance	not provided	2017-07-20	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.1225T>C at the cDNA level, p.Trp409Arg (W409R) at the protein level, and results in the change of a Tryptophan to an Arginine (TGG>CGG). This variant was observed in an individual with diffuse gastric cancer and a family history of signet ring colon cancer (Brooks-Wilson 2004). Studies assessing the functional impact of this variant have found discordant results. While Brooks-Wilson et al. (2004) reported abnormal cell-cell adhesion and collagen invasion on in vitro assays, Petrova et al. (2016) identified cell-cell adhesion and aggregation comparable to wild-type. CDH1 Trp409Arg was also identified in 1/43 healthy African individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. CDH1 Trp409Arg was observed at an allele frequency of 0.006% (4/66740) in individuals of European (Non-Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Tryptophan and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Trp409Arg occurs at a position that is conserved through mammals and is located in Cadherin 3 of the extracellular domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CDH1 Trp409Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000160390	SCV000215116	likely benign	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000205108	SCV000261335	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160390	SCV000684342	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with arginine at codon 409 of the CDH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported conflicting findings on variant impact on cell adhesion (PMID: 15235021, 27582386). This variant has been reported in an individual affected with diffused gastric cancer (PMID: 15235021) and an individual affected with stomach cancer (PMID: 19269290). In a large breast cancer case-control study, the variant has been reported in 0/60466 cases and 2/53461 unaffected controls (PMID: 33471991). It has also been reported as observed in more than 10 individuals without personal or family history of gastric cancer with signet ring cell morphology or lobular breast cancer (ClinVar variation ID: 133855). This variant has been identified in 5/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the available data indicate this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588122	SCV000698355	uncertain significance	not provided	2016-07-01	criteria provided, single submitter	clinical testing	Variant summary: The CDH1 c.1225T>C (p.Trp409Arg) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools utilized predict a damaging outcome for this variant. The residue W409 is found in the third calcium binding domain of the E-cadherin protein at EC2-3 junction, adjacent residue from calcium binding site (Brooks-Wilson_2004, Lee_2014). Consistent with these findings, an in vitro functional study showedthe variant to impact CDH1 functionality by the variant (Brooks-Wilson_2004). This variant was found in 4/121412 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0000599 (4/66740 chromosomes). This frequency is about 2.87 times higher than the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000208), suggesting this variant may be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. However, as CDH1 linked phenotypes (HDGC and HBOC) have generally late-onset (average age of onset >35 years), four individuals with the variant in ExAC may represent reduced penetrance or subclinical cases. This germline variant has been reported in literature in one isolated HDGC patient who also had signet ring cell cancer of the colon (Brooks-Wilson_2004). The patient was also characterized to have promoter methylation + loss of heterozygosity and genotype was considered to be consistent with the phenotype in the patient (Oliveira_2009). Multiple clinical diagnostic laboratories have databases classified this variant as uncertain significance. Taken together, primarily due to some conflicts about pathogenicity of the variant, it is currently classified as Variant of Unknown Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000205108	SCV000890948	likely benign	Hereditary diffuse gastric adenocarcinoma	2020-09-10	criteria provided, single submitter	clinical testing	The c.1225T>C (p. Trp409Arg) missense variant has a frequency of 0.00002 (5 of 251,486 alleles) in gnomAD, with a maximum allele frequency of 0.00004 (5 of 113,762) in the Non-Finnish European subpopulation (http://gnomad.broadinstitute.org). Although this variant was reported in an individual with diffuse gastric cancer and a family history of signet ring colon cancer (PMID: 15235021), these diagnoses do not meet clinical criteria for hereditary diffuse gastric cancer (PMID: 32758476). Data submitted to the ClinGen CDH1 variant curation expert panel indicates that this variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring cell tumors or lobular breast cancer and whose families do not suggest hereditary diffuse gastric cancer (BS2). Six of seven in silico tools predict a deleterious effect of this variant on protein function. While Brooks-Wilson et al. (PMID: 15235021) reported abnormal cell-cell adhesion and collagen invasion on in vitro assays, Petrova et al. (PMID: 26175155) identified cell-cell adhesion and aggregation comparable to wild-type. As the CDH1 variant curation expert panel only approves the use of assays that measure abnormal splicing of the CDH1 gene, functional data was not utilized as evidence of pathogenicity (PMID: 30311375). This variant has been called likely benign by the ClinGen CDH1 Variant Curation Expert Panel (SCV000864607.3). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 2): BS2.
Sema4, Sema4	RCV000160390	SCV002531151	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-04	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002498556	SCV002808566	likely benign	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Neoplasm of ovary; Malignant tumor of prostate	2022-04-08	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492525	SCV004240418	uncertain significance	Breast and/or ovarian cancer	2022-09-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952588	SCV004773169	likely benign	CDH1-related disorder	2020-02-16	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ITMI	RCV000120515	SCV000084668	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358315	SCV001554015	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Trp409Arg variant was identified in 2 of 1448 proband chromosomes (frequency: 0.001) from individuals or families with gastric cancer (Bodian 2014, Brooks-Wilson 2004). The variant was also identified in the following databases: dbSNP (ID: rs587778176) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Color Genomics, LCOA clinical laboratory), and Clinvitae. The variant was not identified in Cosmic, MutDB, or the Zhejiang University Database. The variant was identified in control databases in 5 of 246262 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the European population: in 5 of 111712 chromosomes (freq: 0.0001); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant is found in the third calcium binding domain of the E-cadherin protein and has been shown to lead to loss-of-function in vitro and increased pathogenicity in vivo (Brooks-Wilson 2004, Simoes_Correia 2012). Another functional assay by Petrova (2016) displayed that the variant has no detectable effect on adhesion activation and behaves like WT E-cadherin under various drug treatments. The p.Trp409 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.