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

gnomAD frequency: 0.00045  dbSNP: rs1801025

Total submissions: 21

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	2024-02-01	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
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, part of Exact Sciences	RCV000587811	SCV000806642	likely benign	not provided	2017-04-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212375	SCV000888026	benign	not specified	2021-12-20	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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212375	SCV002551781	likely benign	not specified	2023-08-15	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	RCV000198443	SCV003926846	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2_Supporting; BP2; BP4; BP7 (PMID: 30311375)
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