Submissions for variant NM_004360.5(CDH1):c.2439+10C>T

gnomAD frequency: 0.00057  dbSNP: rs35236080

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123248	SCV000166554	benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000212388	SCV000167599	benign	not specified	2013-12-27	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	RCV000128981	SCV000172867	likely benign	Hereditary cancer-predisposing syndrome	2015-02-12	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.
Counsyl	RCV000123248	SCV000488637	likely benign	Hereditary diffuse gastric adenocarcinoma	2016-05-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128981	SCV000684434	likely benign	Hereditary cancer-predisposing syndrome	2015-04-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588639	SCV000698384	benign	not provided	2016-07-25	criteria provided, single submitter	clinical testing	Variant summary: The CDH1 c.2439+10C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool (MutationTaster) predicts a benign outcome for this variant. 3/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions are not definitive and have not been confirmed by functional studies. This variant was found in 67/120124 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0009851 (65/65982). This frequency is about 35 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. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as Benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000128981	SCV000803169	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000123248	SCV000839098	likely benign	Hereditary diffuse gastric adenocarcinoma	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588639	SCV000889251	benign	not provided	2023-04-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588639	SCV001157630	benign	not provided	2021-05-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262766	SCV001440751	likely benign	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798406	SCV002043272	likely benign	Breast and/or ovarian cancer	2023-06-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212388	SCV002064749	likely benign	not specified	2020-09-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128981	SCV002529138	benign	Hereditary cancer-predisposing syndrome	2020-11-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212388	SCV002551797	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	RCV000123248	SCV003926943	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS1 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000123248	SCV004019598	likely benign	Hereditary diffuse gastric adenocarcinoma	2023-03-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing.
CeGaT Center for Human Genetics Tuebingen	RCV000588639	SCV004140034	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	CDH1: BS1
PreventionGenetics, part of Exact Sciences	RCV003891651	SCV000806660	benign	CDH1-related disorder	2019-06-25	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356066	SCV001551126	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 c.2439+10C>T variant was identified in 1 of 162 proband chromosomes (frequency: 0.006) from individuals or families with non-syndromic orofacial clefts and an unknown family history of hereditary diffuse gastric cancer (Vogelaar 2013). The variant was also identified in dbSNP (ID: rs35236080) as "With other allele" and ClinVar (classified as benign by Invitae, GeneDx and one other clinical laboratory; as likely benign by Ambry Genetics, Counsyl, Color Genomics, and two other clinical laboratories). The variant was not identified in the Zhejiang University Database. The variant was identified in control databases in 142 of 276210 chromosomes (1 homozygous) at a frequency of 0.0005, 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: European in 129 of 126428 chromosomes (freq: 0.001), African in 1 of 23894 chromosomes (freq: 0.00004), Other in 2 of 6448 chromosomes (freq: 0.0003), and Latino in 10 of 34374 chromosomes (freq: 0.0003), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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	RCV000588639	SCV001741016	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000588639	SCV001809482	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000588639	SCV001919287	likely benign	not provided		no assertion criteria provided	clinical testing