ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1744C>T (p.Leu582=)

gnomAD frequency: 0.00045  dbSNP: rs1801025
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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212375 SCV000167596 benign not specified 2014-04-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000124182 SCV000212982 likely benign Hereditary cancer-predisposing syndrome 2016-06-08 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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 RCV000198443 SCV000253411 benign Hereditary diffuse gastric adenocarcinoma 2021-12-17 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000198443 SCV000398568 benign Hereditary diffuse gastric adenocarcinoma 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Genetic Services Laboratory,University of Chicago RCV000212375 SCV000593912 likely benign not specified 2016-10-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212375 SCV000600965 likely benign not specified 2016-12-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000587811 SCV000602951 benign not provided 2017-05-09 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000124182 SCV000684378 likely benign Hereditary cancer-predisposing syndrome 2015-06-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587811 SCV000698372 benign not provided 2017-06-23 criteria provided, single submitter clinical testing Variant summary: The CDH1 c.1744C>T (p.Leu582Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant eliminates ESE binding sites. This variant was found in 37/121410 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000494 (33/66740). This frequency is about 17 times the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. A publication, Ascano_2001, cites the variant to co-occur with another likely pathogenic CDH1 splice-site variant, c.1009-2A>C, along with an co-occurrence in an internal LCA sample that carries two pathogenic MUTYH1 variants, c.536A>G and c.1187G>A. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
PreventionGenetics,PreventionGenetics RCV000587811 SCV000806642 likely benign not provided 2017-04-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587811 SCV000888026 benign not provided 2017-11-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798419 SCV002043256 likely benign Breast and/or ovarian cancer 2019-05-14 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000124182 SCV002529086 benign Hereditary cancer-predisposing syndrome 2021-04-13 criteria provided, single submitter curation
True Health Diagnostics RCV000124182 SCV000787977 likely benign Hereditary cancer-predisposing syndrome 2018-01-12 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358554 SCV001554322 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The CDH1 p.Leu582= variant was identified in 3 of 1236 proband chromosomes (frequency: 0.002) from individuals or families with gastric adenocarcinoma and HDGC (Ascano 2001, van der Post 2015). The variant was also identified in dbSNP (ID: rs1801025) as With other allele, ClinVar (classified as benign by GeneDx, and Integrated Genetics/Laboratory Corporation of America; classified as likely benign by Ambry Genetics, Invitae, ARUP, Color Gnomics, and two clinical laboratories), and Clinvitae databases. The variant was not identified in Cosmic, MutDB, or Zhejiang University Database databases. The variant was identified in control databases in 99 of 277228 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 5 of 24030 chromosomes (freq: 0.0002), European in 91 of 126714 chromosomes (freq: 0.001), Finnish in 3 of 25794 chromosomes (freq: 0.0001), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Leu582= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000587811 SCV001742404 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000587811 SCV001806812 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000587811 SCV001916974 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000587811 SCV001956293 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000587811 SCV001973892 likely benign not provided no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000212375 SCV002551781 likely benign not specified 2022-01-14 no assertion criteria provided clinical testing

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