Submissions for variant NM_004360.5(CDH1):c.933C>G (p.Leu311=)

gnomAD frequency: 0.00974  dbSNP: rs35539711

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328230	SCV001142218	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-08	reviewed by expert panel	curation	The c.933C>G variant has an allele frequency of 0.03128 (3.1%, 781/24,968 alleles) in the African subpopulation of the gnomAD cohort (BA1). 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.
Ambry Genetics	RCV000131958	SCV000187015	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000206365	SCV000262223	benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000206365	SCV000398557	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.
Color Diagnostics, LLC DBA Color Health	RCV000131958	SCV000684496	benign	Hereditary cancer-predisposing syndrome	2015-04-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000583727	SCV000806625	benign	not specified	2016-10-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705935	SCV001477619	benign	not provided	2023-09-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001705935	SCV001873114	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000583727	SCV002551761	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149909	SCV003838414	benign	Breast and/or ovarian cancer	2022-05-25	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	RCV000206365	SCV003926707	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BA1; BS2_Supporting (PMID: 30311375)
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315918	SCV004017015	benign	Malignant tumor of prostate	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001705935	SCV005248445	benign	not provided		criteria provided, single submitter	not provided
Myriad Genetics, Inc.	RCV000206365	SCV005405324	benign	Hereditary diffuse gastric adenocarcinoma	2024-09-17	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	RCV000583727	SCV000691816	benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000131958	SCV000787987	likely benign	Hereditary cancer-predisposing syndrome	2017-09-11	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356813	SCV001552079	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Leu311Leu variant was identified in 3 of 622 proband chromosomes (frequency: 0.005) from individuals or families with early-onset gastric cancer and patients with invasive lobular carcinoma of the breast (Bacani 2006, Valente 2014). The variant was also identified in the following databases: dbSNP (ID: rs35539711) as “With other allele”, ClinVar (3x, as benign by Ambry Genetics and Invitae, as Likely benign by Illumina), Clinvitae (2x, by ClinVar and Invitae). The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Databases. The variant was identified in control databases in 847 of 277200 chromosomes at a frequency of 0.003056 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 776 of 24034 chromosomes (freq: 0.032). The p.Leu311Leu 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 this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000583727	SCV001808333	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000583727	SCV001953645	benign	not specified		no assertion criteria provided	clinical testing