Submissions for variant NM_004360.5(CDH1):c.1680G>C (p.Thr560=)

gnomAD frequency: 0.00261  dbSNP: rs35741240

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000174098	SCV000167595	benign	not specified	2013-12-13	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	RCV000132171	SCV000187250	benign	Hereditary cancer-predisposing syndrome	2014-08-15	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.
Eurofins Ntd Llc (ga)	RCV000174098	SCV000225338	benign	not specified	2015-06-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203779	SCV000262425	benign	Hereditary diffuse gastric adenocarcinoma	2025-02-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000203779	SCV000398566	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001356388	SCV000602949	benign	not provided	2024-07-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132171	SCV000684373	likely benign	Hereditary cancer-predisposing syndrome	2015-04-07	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000203779	SCV000788243	likely benign	Hereditary diffuse gastric adenocarcinoma	2018-01-04	criteria provided, single submitter	clinical testing	CDH1 p.T560T (NM_004360.3:c.1680G>C) has been reported at a frequency of approximately 1 in 100 individuals of European ancestry (exac.broadinstitute.org). This variant frequency is too high to be consistent with the cancer risk syndrome seen with pathogenic CDH1 variants (Hansford 2015). This evidence supports classification of this variant as likely benign. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded.
PreventionGenetics, part of Exact Sciences	RCV000174098	SCV000806640	benign	not specified	2017-01-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000203779	SCV001140146	benign	Hereditary diffuse gastric adenocarcinoma	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798418	SCV002043255	benign	Breast and/or ovarian cancer	2023-06-12	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000174098	SCV002066655	benign	not specified	2021-01-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132171	SCV002529083	benign	Hereditary cancer-predisposing syndrome	2020-08-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000174098	SCV002551777	likely benign	not specified	2025-03-04	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	RCV000203779	SCV003926828	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BA1 (PMID: 30311375)
CeGaT Center for Human Genetics Tuebingen	RCV001356388	SCV004010504	likely benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	CDH1: BP4, BP7, BS2
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315847	SCV004017006	benign	Malignant tumor of prostate	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001356388	SCV005219062	likely benign	not provided		criteria provided, single submitter	not provided
Myriad Genetics, Inc.	RCV000203779	SCV005404161	benign	Hereditary diffuse gastric adenocarcinoma	2024-09-19	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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000203779	SCV005880644	benign	Hereditary diffuse gastric adenocarcinoma	2025-02-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000174098	SCV000691822	benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000132171	SCV000805256	likely benign	Hereditary cancer-predisposing syndrome	2018-04-26	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356388	SCV001551540	likely benign	not provided		no assertion criteria provided	clinical testing	The CDH1 p.Thr560= variant was identified in the literature in 1 of 20 normal chromosomes (frequency: 0.025); however the frequency of this variant in an affected population was not provided (Berx 1997). The variant was also identified in dbSNP (ID: rs35741240) as “With Likely benign, other allele”, in the ClinVar database as benign by GeneDx, Ambry Genetics, EGL Genetic Diagnostics, Invitae, ARUP Laboratories and as likely benign by Illumina Clinical Services; in the Clinvitae database as benign by EmyClass; and in the Cosmic and in Zhejiang Colon Cancer Databases 1X in haemangioblastoma. The variant was not identified in MutDB or the Insight Colon Cancer Gene Variant databases. The variant was further identified in the 1000 Genomes Project in 9 of 5000 chromosomes (frequency: 0.002) and in the NHLBI GO Exome Sequencing Project in 25 of 8600 European American and 3 in 4396 in African American alleles. The variant was identified in control databases in 925 of 277220 chromosomes (4 homozygous) at a frequency of 0.003 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 19 of 24022 chromosomes (freq: 0.0008), other in 14 of 6464 chromosomes (freq: 0.002), Latino in 46 of 34420 chromosomes (freq: 0.001), European Non-Finnish in 573 of 126722 chromosomes (freq: 0.004), Ashkenazi Jewish in 8 of 10152 chromosomes (freq: 0.0008), East Asian in 2 of 18868 chromosomes (freq: 0.0001), European Finnish in 52 of 25794 chromosomes (freq: 0.002), and South Asian in 211 of 30778 chromosomes (freq: 0.007). The p.Thr560= 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	RCV001356388	SCV001744663	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001356388	SCV001807884	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001356388	SCV001921994	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000174098	SCV001951038	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001356388	SCV001973289	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001356388	SCV002036348	likely benign	not provided		no assertion criteria provided	clinical testing