rs200894246
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The c.2413G>A (p.Asp805Asn) variant has an allele frequency of 0.00207 (0.21%, 21/10,148 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157966/MONDO:0007648/007
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2413G>A | p.Asp805Asn | missense_variant | 15/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2230G>A | p.Asp744Asn | missense_variant | 14/15 | ||
CDH1 | NM_001317185.2 | c.865G>A | p.Asp289Asn | missense_variant | 15/16 | ||
CDH1 | NM_001317186.2 | c.448G>A | p.Asp150Asn | missense_variant | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2413G>A | p.Asp805Asn | missense_variant | 15/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000257 AC: 39AN: 151890Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000239 AC: 60AN: 251276Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135822
GnomAD4 exome AF: 0.000243 AC: 355AN: 1461840Hom.: 0 Cov.: 32 AF XY: 0.000223 AC XY: 162AN XY: 727232
GnomAD4 genome ? AF: 0.000257 AC: 39AN: 151890Hom.: 0 Cov.: 32 AF XY: 0.000270 AC XY: 20AN XY: 74158
ClinVar
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:1Benign:5
Benign, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 09, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto | Aug 01, 2022 | BA1; BS2_Suportive (PMID: 30311375) - |
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Aug 15, 2016 | Originally interpreted based on literature review PMID: 25637381. Found in a female patient having exome sequencing for an unrelated indication. No known history of diffuse gastric cancer or breast cancer. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 06, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 17, 2019 | This alteration is classified as 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 01, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | May 03, 2023 | - - |
not specified Benign:4Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 08, 2021 | Variant summary: CDH1 c.2413G>A (p.Asp805Asn) results in a conservative amino acid change located in the Cadherin, cytoplasmic domain (IPR000233) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 251938 control chromosomes. The observed variant frequency is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is benign. c.2413G>A has been reported in the literature in a family with gastric and diffuse gastric cancer in an unaffected patient; however the age was not provided (Hansford_2015). An additional CDH1 variant (c.2430delT) was also identified in a proband affected with DGC in this family. This variant was also observed associated with non-syndromic cleft-palate, Lynch Syndrome, pancreatic ductal adenocarcinoma, and NSCLC patients without strong evidence for causality (Vogelaar_2013, Yurgelun_2015, Yurgelun_2017, Rangachari_2015, Shindo_2017, Shirts_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.7618-1G>A), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Vogelaar_2013). The most pronounced variant effect results in slightly impaired cell invasion suppression, displaying smaller cellular aggregates than the WT and to result in reduced membranous E-cadherin expression while not affecting the expression level of CDH1. However, the clinical relevance of these functional impacts is uncertain. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments with a majority consensus leaning towards benign/likely benign (n=8). Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 26, 2021 | - - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | CDH1: BP1, BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2021 | This variant is associated with the following publications: (PMID: 29348693, 25980754, 25862857, 24728327, 25637381, 26601054, 26845104, 26580448, 26182300, 23197654, 28135145, 28873162, 28767289) - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 05, 2023 | - - |
CDH1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 16, 2021 | 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
Benign, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 08, 2023 | The c.2413G>A (p.Asp805Asn) variant has an allele frequency of 0.00207 (0.21%, 21/10,148 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1. - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CDH1 p.Asp805Asn variant was identified in 2 of 2886 proband chromosomes (frequency: 0.0007) from individuals or families with hereditary diffuse gastric cancer or Lynch syndrome and was present in 1 of 1362 control chromosomes (frequency: 0.0007) from healthy individuals (Bodian 2014, Hansford 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs200894246) as "With other allele", ClinVar (classified as benign by Invitae; as likely benign by GeneDx and Ambry Genetics; as uncertain significance by four submitters). The variant was identified in control databases in 63 of 276968 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 6460 chromosomes (freq: 0.0003), Latino in 13 of 34404 chromosomes (freq: 0.0004), European in 26 of 126584 chromosomes (freq: 0.0002), Ashkenazi Jewish in 21 of 10148 chromosomes (freq: 0.002), and South Asian in 1 of 30770 chromosomes (freq: 0.00003), while the variant was not observed in the African, East Asian, and Finnish, populations. One study performed in vitro functional assay (Vogelaar 2013) and found that the variant p.Asp805Asn affects E-cadherin protein function and its subcellular localization and can be considered as a pathogenic mutation however result have no additional functional work supports this claim and more over this missense variant and similar ones in this study have been found in families without a clinical phenotype suggesting that the in vitro data does not reflect the clinical impact of the variants. The p.Asp805 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Familial cancer of breast;C1708349:Hereditary diffuse gastric adenocarcinoma Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 04-08-2016 by Lab Quest Diagnostics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at