ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2343A>T (p.Glu781Asp) (rs587780119)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000234640 SCV001437608 likely benign Hereditary diffuse gastric cancer 2020-08-19 reviewed by expert panel curation The c.2343A>T (p.Glu781Asp) missense variant has a frequency of 0.00001 (4 of 282,860) in gnomAD, with a maximum allele frequency of 0.00004 (1 of 24,970) in the African subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in ≥100 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000149761.14, SCV000185618.5, SCV000288464.7). Although functional impact of this variant was reported from in vitro assays, functional assays except splicing assay are not applicable to CDH1 according to the CDH1 specific variant interpretation criteria. 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 2): BS2.
GeneDx RCV000225693 SCV000149761 uncertain significance not provided 2018-12-18 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.2343A>T at the cDNA level, p.Glu781Asp (E781D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAT). This variant has been suggested in several in vitro assays to result in instability of E-cadherin at the plasma membrane with a possible effect on cell-cell adhesion (Figueiredo 2013, Sanches 2014). However, results of in vitro invasion assays are not consistent (Kaurah 2007, Figueiredo 2013) and an in vitro motility assay concluded that CDH1 Glu781Asp functioned similar to a wild-type control (Mateus 2009). While this variant has been reported in two unaffected individuals with family histories of gastric cancer and one individual with a personal history of gastric cancer, segregation analysis was not completed in these families (Kaurah 2007, Benusiglio 2013, Reuter 2018). CDH1 Glu781Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the p120-catenin and Hakai binding regions within the cytoplasmic domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. While there are a few in vitro functional assays suggesting pathogenicity, internal observations at this and other clinical laboratories are not suggestive of hereditary diffuse gastric cancer (ClinVar SCV000288464, ClinVar SCV000185618). Based on currently available evidence, it is unclear whether CDH1 Glu781Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115852 SCV000185618 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-28 criteria provided, single submitter clinical testing The p.E781D variant (also known as c.2343A>T), located in coding exon 15 of the CDH1 gene, results from an A to T substitution at nucleotide position 2343. The glutamic acid at codon 781 is replaced by aspartic acid, an amino acid with highly similar properties. This variant has been reported in 2/203 families with a history of diffuse gastric cancer (Kaurah P et al. JAMA. 2007 Jun;297:2360-72; Benusiglio PR et al. J. Med. Genet. 2013 Jul;50:486-9). In the Kaurah et al. study, Chinese hamster ovary (CHO) cells expressing this variant failed to produce compact cellular aggregates and had significantly higher invasion into collagen matrices than wild-type, suggesting impaired function of epithelial E-cadherin. A second study using gastric cancer cell lines expressing this variant, which occurs in the cytoplasmic-tail region of the protein, suggested that this variant does not impair the ability of E-cadherin to suppress cell migration (Mateus AR et al. Exp. Cell Res. 2009 May;315:1393-402). However, a more recent functional study performed on this variant demonstrated that this variant affects the interaction of cytoplasmic E-cadherin with three binding partners, compromising its stability at the plasma membrane, and is likely to affect the adhesion complex competence (Figueiredo J et al. Eur. J. Hum. Genet. 2013 Mar;21:301-9). This alteration has also been reported in 1/620 women with a family history of breast and/or ovarian cancer (Schroeder C et al. Breast Cancer Res. Treat. 2015 Jul;152:129-136). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence for this variant is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000234640 SCV000288464 uncertain significance Hereditary diffuse gastric cancer 2020-10-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 781 of the CDH1 protein (p.Glu781Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs587780119, ExAC 0.001%). This variant has been reported in individual(s) with breast cancer (PMID: 26022348, 30374176), and in two individuals with a family history of diffuse gastric cancer and/or lobular breast cancer (PMID: 17545690, 23709761). ClinVar contains an entry for this variant (Variation ID: 127923). Functional experiments for this variant are conflicting. Two studies demonstrate that this missense change interferes with cellular aggregation and increases cellular invasion into collagen matrices (PMID: 17545690, 22850631), while a third study reports normal cell motility (PMID: 19268661). 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.
Counsyl RCV000234640 SCV000489546 uncertain significance Hereditary diffuse gastric cancer 2016-10-21 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000234640 SCV000890963 likely benign Hereditary diffuse gastric cancer 2020-09-09 criteria provided, single submitter clinical testing The c.2343A>T (p.Glu781Asp) missense variant has a frequency of 0.00001 (4 of 282,860 alleles) in gnomAD, with a maximum allele frequency of 0.00004 (1 of 24,970) in the African subpopulation (http://gnomad.broadinstitute.org). Data submitted to the ClinGen CDH1 variant curation expert panel indicates that this variant has been observed in greater than or equal to 100 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; SCV000149761.14, SCV000185618.5, SCV000288464.7). Five of seven in silico tools predict a benign effect of this variant on protein function. Functional assays have indicated mixed effects of this variant on cellular processes. This variant has been suggested to result in a reduction of binding with p120-catenin and reduced expression of E-cadherin protein encoded by CDH1 (PMIDs: 25388006, 22850631). An in vitro motility assay concluded that the E781D mutant functioned similar to a wild-type control (PMID: 19268661). 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 applied as evidence of pathogenicity (PMID: 30311375). 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.
Color Health, Inc RCV000115852 SCV000910792 likely benign Hereditary cancer-predisposing syndrome 2017-02-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780095 SCV000917132 uncertain significance not specified 2020-07-22 criteria provided, single submitter clinical testing Variant summary: CDH1 c.2343A>T (p.Glu781Asp) results in a conservative amino acid change located in the cytoplasmic domain (IPR000233) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251468 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2343A>T has been reported in the literature in individuals with a personal or family history of diffuse gastric cancer, and also in individuals affected with other tumor phenotypes, however without strong evidence for causality (Xie_2011, Ring_2016, Kaurah_2007, Benusiglio_2013, Reuter_2018). Co-occurrence with another pathogenic variant has been reported in an endometrial cancer case (BARD1 c.1690C>T (p.Gln564*; Ring_2016), providing supporting evidence for a benign role. Several publications functionally evaluated the variant and its effect on cell motility, cell aggregation, cell invasion, p120 binding, EGFR activation, protein localization at the plasma membrane, and protein expression. These studies provide conflicting results, ranging from defective cell aggregation and protein localization at plasma membrane, increased cell invasion, normal cellular motility and normal EGFR activation, making interpretation of the data difficult (Figueiredo_2013, Kaurah_2007, Mateus_2009, Sanches_2015). Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000225693 SCV001134077 uncertain significance not provided 2020-01-28 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000234640 SCV001446373 likely benign Hereditary diffuse gastric cancer 2019-06-10 no assertion criteria provided research

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