rs587780537
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4PS3PP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.715G>A (p.Gly239Arg) variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 16 families (18) meeting HDGC clinical criteria (PS4_very strong; PMID:17545690, 23264079, 23264079, 26182300; SCV000153869.9, SCV000273881.6, internal laboratory contributors). This variant is predicted to affect splicing by at least 3 in silico splicing predictors in agreement (PP3). There are RNA assays demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID:17545690, 33619332). 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 (v3.1): PS4_very strong, PS3, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA298980/MONDO:0007648/007
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CDH1
NM_004360.5 missense
NM_004360.5 missense
Scores
5
12
2
Clinical Significance
Conservation
PhyloP100: 6.30
Genes affected
CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CDH1 | NM_004360.5 | c.715G>A | p.Gly239Arg | missense_variant | 6/16 | ENST00000261769.10 | NP_004351.1 | |
| CDH1 | NM_001317184.2 | c.715G>A | p.Gly239Arg | missense_variant | 6/15 | NP_001304113.1 | ||
| CDH1 | NM_001317185.2 | c.-901G>A | 5_prime_UTR_variant | 6/16 | NP_001304114.1 | |||
| CDH1 | NM_001317186.2 | c.-1105G>A | 5_prime_UTR_variant | 6/15 | NP_001304115.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CDH1 | ENST00000261769.10 | c.715G>A | p.Gly239Arg | missense_variant | 6/16 | 1 | NM_004360.5 | ENSP00000261769.4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727236
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1461860
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 13, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 239 of the CDH1 protein (p.Gly239Arg). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with breast and/or diffuse gastric cancer (PMID: 17221870, 17545690, 23264079, 26681312, 26845104, 28873162, 32269045; Invitae). ClinVar contains an entry for this variant (Variation ID: 132709). 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: 17221870, 17545690, 19268661, 27582386, 30311375). Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 17545690, 33619332; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 26, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 22, 2018 | Variant summary: CDH1 c.715G>A (p.Gly239Arg) results in a non-conservative amino acid change located in the Cadherin domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict that the variant creates a 3' acceptor site without a significant impact on the canonical splicing site. One publication reports experimental evidence that this variant affects mRNA splicing, causing the deletion of the first 29 base pairs from exon 6 (validated by minigene analysis)(Kaurah_2007) (ACMG PP3 and ACMG PS3 consistent with ClinGen recommendations by Lee_CDH1_Human Mut_2018). The variant was absent in 246230 control chromosomes (gnomAD) (ACMG PM2). The variant, c.715G>A, has been reported in the literature in multiple individuals and families affected with Hereditary Diffuse Gastric Cancer, where it segregated with disease (Kaurah_CDH1_JAMA_2007, Shirts_2016, Mandelker_2017, Kim_2013) and in one Breast Cancer case (Susswein_2016). However, it was also found in a family in which a 79 yo individual carrying this variant was disease-free, suggesting reduced penetrance (More_2007). Overall, these data indicate that the variant is likely to be associated with disease (ACMG PS4 consistent with ClinGen recommendations by Lee_CDH1_Human Mut_2018). Functional studies showed that this variant is associated with deficient E-cadherin function with no significant/moderate changes in protein expression levels (More_2007, Kim_2013), increased motility with reduced affinity for EGFR and higher EGFR activation (Mateus_2009, Figueiredo_2010). However, one other study showed that this variant does not affect adhesion but affects transduction of signaling across the membrane (Petrova_2016). In accordance with the ClinGen recommendations, we did not use functional assays for missense variants as evidence for CDH1 variant classification. However, the variant still meets the ClinGen recommended ACMG PS3 criteria as it results in an abnormal out of frame transcript as discussed above. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS 1x, likely pathogenic/pathogenic 5x). Based on the evidence outlined above, the variant was classified as pathogenic and also consistent with the ClinGen recommended criteria for CDH1 variant classification (ACMG PS3, PS4, PM2, PP3). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 07, 2023 | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [17221870, 17545690, 23264079, 26182300, Myriad internal data]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [17545690, Myriad internal data]. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 01, 2020 | This missense variant replaces glycine with arginine at codon 239 in the extracellular domain of the CDH1 protein. A functional study has shown that this variant disrupts RNA splicing and causes a deletion of the first 29 bases of exon 6 in cells isolated from a carrier individual as well as in minigene assay (PMID: 17545690). This aberrant splicing is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with diffuse gastric cancer (PMID: 17221870, 17545690, 23264079, 26845104) and breast cancer (PMID: 26681312). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 19, 2022 | The p.G239R pathogenic mutation (also known as c.715G>A), located in coding exon 6 of the CDH1 gene, results from a G to A substitution at nucleotide position 715. The glycine at codon 239 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with either a personal history of early onset diffuse gastric cancer and/or a family history consistent with hereditary diffuse gastric cancer syndrome (Kim S et al. Fam. Cancer. 2013 Sep;12:503-7; More H et al. Hum. Mutat. 2007 Feb;28:203; Suriano GJ et al. J. Mol. Med. 2006 Dec;84:1023-31; Ambry internal data); but has also been reported in unaffected individuals (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; More H et al. Hum. Mutat. 2007 Feb;28:203). Protein studies have shown that this alteration confers deficient E-cadherin function with respect to intercellular adhesion and suppression of invasion in vitro (More H et al. Hum. Mutat. 2007 Feb;28:203), motility (Mateus AR et al. Exp. Cell Res. 2009 May;315:1393-402), and adhesion activation from intracellular triggers (Petrova YI et al. Mol. Biol. Cell, 2016 Nov;27:3233-3244). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. RNA studies have detected an abnormal out of frame transcript with the first 29 base pairs of exon 6 deleted in individuals with this alteration (Kaurah P et al. JAMA. 2007 Jun;297:2360-72, Ambry internal data). Based on the available evidence, this alteration is classified as a pathogenic mutation. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 05, 2023 | The CDH1 c.715G>A (p.Gly239Arg) variant has been reported in the published literature in individuals with gastric cancer (PMID: 16924464 (2006), 17221870 (2007), 17545690 (2007), 23264079 (2013), 28873162 (2017), 32269045 (2020), 33619332 (2021)), breast cancer (PMID: 26681312 (2015), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CDH1), 34949788 (2022)), pancreatic cancer (PMID: 29922827 (2018)), and prostate cancer (PMID: 34949788 (2022)). This variant has also been reported in an unaffected individual (PMID: 17221870 (2007)). Splicing studies have reported this variant abolishes normal splicing through activation of a cryptic 3' acceptor splice site, leading to an out-of-frame deletion that results in premature protein truncation (PMID: 33619332 (2021), 17545690 (2007)). Functional studies of this variant's effect on CDH1 function are conflicting (PMID: 17221870 (2007), 19268661 (2009), 27582386 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on CDH1 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 17, 2021 | Identified in patients with diffuse gastric cancer, but also in unaffected relatives (Kaurah 2007, More 2007, Kim 2013, Wang 2020); RNA studies demonstrate abnormal splicing, with an out-of-frame deletion of the first 29 base pairs of exon 6 being the most abundant transcript as well as a small amount of full-length transcript harboring the G293R missense change (Kaurah 2007, Yelskaya 2021); Published functional studies demonstrate a negative impact on E-cadherin function with respect to suppression of invasion, increased cell motility, increased EGFR activation, and intracellular signaling; however, there have been mixed results regarding its impact on intercellular adhesion (More 2007, Mateus 2009, Petrova 2016); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 23264079, 26681312, 16924464, 17221870, 20373070, 22098830, 26845104, 26182300, 28873162, 29577179, 31246251, 33809393, 15235021, 22850631, 34012620, 31511843, 32269045, 19268661, 27582386, 17545690, 33619332) - |
Familial cancer of breast;C0376358:Malignant tumor of prostate;C0476089:Endometrial carcinoma;C0919267:Ovarian neoplasm;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 03, 2022 | - - |
CDH1-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 16, 2024 | The CDH1 c.715G>A variant is predicted to result in the amino acid substitution p.Gly239Arg. This variant has been reported in individuals with diffuse gastric cancer (More et al. 2007. PubMed ID: 17221870; Kaurah et al. 2007. PubMed ID: 17545690; Kim et al. 2013. PubMed ID: 23264079). It was also reported in individuals with breast cancer (Table S1 at Susswein et al. 2016. PubMed ID: 26681312). This change is predicted to affect normal splicing and this effect was confirmed by RT-PCR analysis and minigene studies (Kaurah et al. 2007. PubMed ID: 17545690). Functional studies showed that this variant resulted in increased matrigel invasion, enhanced cell motility, and increased EGFR activation (More et al. 2007. PubMed ID: 17221870; Mateus et al. 2009. PubMed ID: 19268661; Petrova et al. 2016. PubMed ID: 27582386). This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/132709/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1
| Pathogenic, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 29, 2023 | The c.715G>A (p.Gly239Arg) variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 16 families (18) meeting HDGC clinical criteria (PS4_very strong; PMID: 17545690, 23264079, 23264079, 26182300; SCV000153869.9, SCV000273881.6, internal laboratory contributors). This variant is predicted to affect splicing by at least 3 in silico splicing predictors in agreement (PP3). There are RNA assays demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 17545690, 33619332). 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 (v3.1): PS4_very strong, PS3, PM2_supporting, PP3. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;T;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.;.;.;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;.;D
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;.;.;.;.
Vest4
MutPred
Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at