chr16-68813400-T-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157989/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.1225T>C | p.Trp409Arg | missense_variant | 9/16 | ENST00000261769.10 | |
CDH1 | NM_001317185.2 | c.-391T>C | 5_prime_UTR_variant | 9/16 | |||
CDH1 | NM_001317186.2 | c.-595T>C | 5_prime_UTR_variant | 9/15 | |||
CDH1 | NM_001317184.2 | c.1137+1137T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.1225T>C | p.Trp409Arg | missense_variant | 9/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152058Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251486Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135916
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727234
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74244
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 05, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 04, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2020 | 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 01, 2016 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2017 | 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. - |
Hereditary diffuse gastric adenocarcinoma Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 10, 2020 | 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. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 22, 2022 | - - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Familial cancer of breast;C0376358:Malignant tumor of prostate;C0476089:Endometrial carcinoma;C0919267:Ovarian neoplasm;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 08, 2022 | - - |
CDH1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 16, 2020 | 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). - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 17, 2023 | 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. - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at