Submissions for variant NM_004360.5(CDH1):c.324A>G (p.Arg108=)

gnomAD frequency: 0.00255  dbSNP: rs116542018

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328196	SCV001365450	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-10	reviewed by expert panel	curation	The NM_004360.5(CDH1):c.324A>G (p.Arg108=) variant has an allele frequency of 0.00769 (0.769%, 192/24966 alleles) in the African subpopulation and one homozygote in the European (Non-Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, 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, BP2.
GeneDx	RCV000212349	SCV000167588	benign	not specified	2014-01-06	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	RCV000124174	SCV000213147	likely benign	Hereditary cancer-predisposing syndrome	2014-06-17	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079438	SCV000252794	benign	Hereditary diffuse gastric adenocarcinoma	2025-02-04	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000212349	SCV000340103	benign	not specified	2016-02-29	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000124174	SCV000679729	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000124174	SCV000684454	benign	Hereditary cancer-predisposing syndrome	2015-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588054	SCV000698395	benign	not provided	2016-04-11	criteria provided, single submitter	clinical testing	Variant summary: Variant Summary: The c.324G>A (p.Arg108=) in CDH1 gene is a synonymous change that involves a non-conserved nucleotide with a prediction of being a "disease-causing" by mutation taster. 3/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at an overall allele frequency of 0.1% (126/121336 chrs tested), mainly in individuals of African descent (0.83%; 86/10384 chrs tested). The observed frequency exceeds the maximum expected allele frequency for a pathogenic CDH1 variant (0.0028%), suggesting that it is a common polymorphism. Based on the published reports, the variant of interest was found in affected individuals as well as in unaffected controls. Lastly, the variant has been reported as Benign by multiple reputable database/clinical laboratories. Taken together, the variant was classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000212349	SCV000806664	benign	not specified	2017-06-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588054	SCV002049892	benign	not provided	2021-05-08	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212349	SCV002064806	benign	not specified	2021-10-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000124174	SCV002529170	benign	Hereditary cancer-predisposing syndrome	2020-10-26	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212349	SCV002760851	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149855	SCV003837762	benign	Breast and/or ovarian cancer	2023-02-27	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	RCV001079438	SCV003927020	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BA1; BS2; BP2_Strong (PMID: 30311375)
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315845	SCV004017018	benign	Malignant tumor of prostate	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588054	SCV004701811	benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	CDH1: BP4, BP7, BS1, BS2
Myriad Genetics, Inc.	RCV001079438	SCV005405287	benign	Hereditary diffuse gastric adenocarcinoma	2024-09-12	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000212349	SCV000691812	likely benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355320	SCV001550178	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Arg108= variant was identified in 3 of 594 proband chromosomes (frequency: 0.005) from Canadian and Brazilian individuals or families with early-onset gastric cancer or nonsyndromic orofacial cleft (reportedly associated with gastric cancer), and in 6 of 1218 chromosomes (frequency: 0.005) from healthy individuals (Bacani_2006_16801346, Brito_2015_26123647, ). The variant was also identified in dbSNP (ID: rs116542018) “With Likely benign allele”, ClinVar (classified benign by GeneDx, Invitae and EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), and likely benign by Ambry Genetics), Clinvitae (4x), Insight Colon Cancer Gene Variant Database (2x), and in control databases in 288 (1 homozygous) of 276950 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 187 of 24030 chromosomes (freq: 0.008), Other in 4 of 6462 chromosomes (freq: 0.0006), Latino in 32 of 34418 chromosomes (freq: 0.0009), European Non-Finnish in 43 (1 homozygous) of 126460 chromosomes (freq: 0.0003), East Asian in 1 of 18866 chromosomes (freq: 0.00005), European Finnish in 20 of 25792 chromosomes (freq: 0.0008), and South Asian in 1 of 30780 chromosomes (freq: 0.00003), while not observed in the Ashkenazi Jewish population. The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The p.Arg108= 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 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000212349	SCV001806811	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588054	SCV001955512	likely benign	not provided		no assertion criteria provided	clinical testing