Submissions for variant NM_004360.5(CDH1):c.1774G>A (p.Ala592Thr)

gnomAD frequency: 0.00311  dbSNP: rs35187787

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328161	SCV000864579	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-08	reviewed by expert panel	curation	The c.1774G>A (p.Ala592Thr) variant has an allele frequency of 0.00481 (0.48%, 609/126,710 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort (BA1). In summary, 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.
GeneDx	RCV000120499	SCV000149755	benign	not specified	2017-05-22	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119222	SCV000153966	benign	Hereditary diffuse gastric adenocarcinoma	2025-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115846	SCV000212796	benign	Hereditary cancer-predisposing syndrome	2014-12-17	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.
Vantari Genetics	RCV000115846	SCV000267031	benign	Hereditary cancer-predisposing syndrome	2015-12-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000119222	SCV000398569	likely benign	Hereditary diffuse gastric adenocarcinoma	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034704	SCV000610263	likely benign	not provided	2017-06-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115846	SCV000684379	likely benign	Hereditary cancer-predisposing syndrome	2014-12-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120499	SCV000806643	benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000119222	SCV000839090	likely benign	Hereditary diffuse gastric adenocarcinoma	2018-07-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034704	SCV001150955	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	CDH1: BP4, BS2
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034704	SCV002009861	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798068	SCV002043257	likely benign	Breast and/or ovarian cancer	2022-01-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034704	SCV002049347	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120499	SCV002066666	benign	not specified	2021-04-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115846	SCV002529087	benign	Hereditary cancer-predisposing syndrome	2020-05-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120499	SCV002551782	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496520	SCV002810160	likely benign	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2021-08-04	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	RCV000119222	SCV003926853	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BA1 (PMID: 30311375)
Breakthrough Genomics, Breakthrough Genomics	RCV000034704	SCV005251505	benign	not provided		criteria provided, single submitter	not provided
Myriad Genetics, Inc.	RCV000119222	SCV005404171	benign	Hereditary diffuse gastric adenocarcinoma	2024-09-20	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV003328161	SCV000043245	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-10-03	no assertion criteria provided	research	BA1 based on allele frequency in NFE of 0.00472 in gnomAD.
ITMI	RCV000120499	SCV000084652	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000119222	SCV000189916	likely benign	Hereditary diffuse gastric adenocarcinoma	2014-07-24	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148453	SCV000190152	likely benign	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000120499	SCV000691823	likely benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000115846	SCV000886679	benign	Hereditary cancer-predisposing syndrome	2018-08-07	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120499	SCV001551983	benign	not specified		no assertion criteria provided	clinical testing	The CDH1 p.Ala592Thr variant was identified in 19 of 5458 proband chromosomes (frequency: 0.003) from individuals or families with gastric, breast and ovarian cancers; and was present in 8 of 1472 control chromosomes (frequency: 0.005) from healthy individuals (Garziera 2013, Huiping 2001, Salahshor 2001, Schrader 2011, Stuebs 2017, Valente 2014). The variant was also identified in dbSNP (ID: rs35187787) as “with Uncertain significance, other allele”. In addition, the variant was identified in the ClinVar and Clinvitae database (as likely benign by GeneDx, Illumina clinical Services, Centre for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Pathway Genomics, CSER, University of Washington; as benign by Invitae, Ambry Genetics, Vantari Genetics; and with uncertain significance by Biesecker Lab/Human Development Section, NIH). The variant was also listed in the Cosmic database 4x as pathogenic with a FATHMM prediction score of 0.99; in the Insight Colon Cancer Gene Variant Database 6x (frequency 0.003), and in the Zhejiang Colon Cancer Database 3x. The variant was not identified in the MutDB database. Furthermore, the variant was also listed in the 1000 Genomes Project in 6 of 5000 chromosomes (frequency: 0.001) and in the NHLBI GO Exome Sequencing Project in 54 of 8600 European American alleles and in 5 of 4396 African American alleles. The variant was identified in control databases in 893 of 277218 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). It was observed in the following populations: African in 21 of 24028 chromosomes (freq: 0.0009), Other in 24 of 6464 chromosomes (freq: 0.004), Latino in 65 of 34420 chromosomes (freq: 0.002), European Non-Finnish in 609 of 126710 chromosomes (freq: 0.005), Ashkenazi Jewish in 30 of 10152 chromosomes (freq: 0.003), Finnish in 43 of 25794 chromosomes (freq: 0.002), and South Asian in 101 of 30782 chromosomes (freq: 0.003); while the variant was not observed in the East Asian population. In one study, the frequency (0.06, n=3) of the p.Ala592Thr variant in 50 gastric tumors is almost four-fold that in normal population, suggesting that this variant indeed contributed to the tumorigenesis in a subset of gastric tumors. The authors concluded that the p.Ala592Thr variant may increase the lifetime risk of developing gastric cancer as a low penetrance variant (Huiping 2001). However allelic association studies do not support an effect of this alteration in predisposing to breast cancer in general as the variant was seen at similar frequencies between case and control groups (Salahshor 2001). In further research the p.Ala592Thr variant was again identified in both cases and controls, suggesting an improbable effect on gastric cancer pathogenesis. (Garziera 2013). In addition functional studies also support a non-pathogenic role; the p.Ala592Thr variant shows no detectable effect on adhesion activation and behaves like wild-type E-cadherin when treated with adhesion activating reagents (Petrova 2016), and cells expressing the E-cadherin variant behave like wild-type in regards to migration and aggregation (Kreller 2004). The p.Ala592 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000034704	SCV001741803	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000034704	SCV001809739	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000034704	SCV001920226	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034704	SCV001952587	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000034704	SCV002036692	likely benign	not provided		no assertion criteria provided	clinical testing