Submissions for variant NM_004360.5(CDH1):c.2589C>T (p.Asn863=)

gnomAD frequency: 0.00022  dbSNP: rs115817750

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123250	SCV000166557	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000212392	SCV000167600	benign	not specified	2013-12-18	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	RCV000124185	SCV000213222	likely benign	Hereditary cancer-predisposing syndrome	2014-08-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Illumina Laboratory Services, Illumina	RCV000123250	SCV000398585	likely benign	Hereditary diffuse gastric adenocarcinoma	2018-01-13	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Counsyl	RCV000123250	SCV000487911	likely benign	Hereditary diffuse gastric adenocarcinoma	2015-12-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000124185	SCV000537421	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	RCV000589458	SCV000698390	benign	not provided	2016-08-08	criteria provided, single submitter	clinical testing	Variant summary: The c.2589C>T (p.Asn863=) in CDH1 gene is a synonymous change that involves a non-conserved nucleotide. The variant is present in the control population dataset of ExAC at frequency of 0.00016 (19/121410 chrs tested). This frequency exceeds the maximal expected frequency of a pathogenic allele (0.000028) in this gene. The variant of interest was cited as Likely Benign/Benign by reputable database/clinical laboratories. Taking together, the variant was classified as Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589458	SCV000889257	benign	not provided	2023-08-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000124185	SCV002529155	benign	Hereditary cancer-predisposing syndrome	2020-12-02	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149843	SCV003837772	likely benign	Breast and/or ovarian cancer	2021-09-03	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	RCV000123250	SCV003926966	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BP7 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000123250	SCV004019600	benign	Hereditary diffuse gastric adenocarcinoma	2023-03-06	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
CeGaT Center for Human Genetics Tuebingen	RCV000589458	SCV004184579	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	CDH1: BP4, BP7
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212392	SCV005090257	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355157	SCV001549952	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Asn863= variant was not identified in the literature nor was it identified in the Cosmic, MutDB, Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs115817750) as With Likely benign, Uncertain significance allele, ClinVar (classified as likely benign by Invitae, Ambry Genetics, Counsyl, Color Genomics; classified as benign by GeneDx, IGLCA). The variant was identified in control databases in 49 of 277226 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 8 of 24032 chromosomes (freq: 0.0003), European in 37 of 126712 chromosomes (freq: 0.0003), East Asian in 4 of 18870 chromosomes (freq: 0.0002); it was not observed in the Other, Latino, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Asn863= 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.