Submissions for variant NM_004360.5(CDH1):c.1409C>T (p.Thr470Ile)

gnomAD frequency: 0.00012  dbSNP: rs370864592

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328170	SCV000864605	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-10	reviewed by expert panel	curation	The c.1409C>T (p.Thr470Ile) variant was observed in trans with a known pathogenic CDH1 variant with phase confirmed (BP2_Strong; PMID: 9537325). This variant was also observed in the homozygous state in at least 6 individuals without a personal and/or family history of diffuse gastric cancer, signet ring cell tumor or lobular breast cancer (BP2_Strong; internal laboratory contributors). Additionally, this variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). 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): BP2_Strong, BS2.
GeneDx	RCV000200980	SCV000149750	likely benign	not specified	2017-11-07	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	RCV000123236	SCV000166542	benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115841	SCV000186634	benign	Hereditary cancer-predisposing syndrome	2019-01-17	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.
Color Diagnostics, LLC DBA Color Health	RCV000115841	SCV000537443	likely benign	Hereditary cancer-predisposing syndrome	2015-08-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590637	SCV000698362	benign	not provided	2017-08-16	criteria provided, single submitter	clinical testing	Variant summary: The CDH1 c.1409C>T (p.Thr470Ile) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 4/121516 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.000347 (3/8654). This frequency is about 12 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 East Asian origin. The variant has been reported in affected individuals in the literature, without strong evidence for causality. One publication cites the variant in a gastric cancer family who also carried a pathogenic CDH1 variant, and the authors state the variant of interest did not co-segregate with disease in this family (Garziera_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as benign.
Counsyl	RCV000123236	SCV000786453	likely benign	Hereditary diffuse gastric adenocarcinoma	2018-05-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590637	SCV000888022	benign	not provided	2022-07-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115841	SCV002529062	likely benign	Hereditary cancer-predisposing syndrome	2021-05-27	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002505036	SCV002809573	likely benign	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2022-03-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149805	SCV003838418	uncertain significance	Breast and/or ovarian cancer	2022-07-05	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	RCV000123236	SCV003926790	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2; BP2_Strong (PMID: 30311375)
Myriad Genetics, Inc.	RCV000123236	SCV004020038	likely benign	Hereditary diffuse gastric adenocarcinoma	2023-03-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000200980	SCV005090245	benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000123236	SCV000493724	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2015-09-26	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000200980	SCV001550607	benign	not specified		no assertion criteria provided	clinical testing	The CDH1 p.Thr470Ile variant was identified in 1 of 118 proband chromosomes (frequency: 0.008) from individuals or families with Gastric Cancer (Garziera 2013) and in 1 of 276 control chromosomes for an oral cleft study (Ittiwut, 2016). This variant was observed in population databases at an overall frequency of 0.00003 (Exome Aggregation Consortium, Genome Aggregation Database). This variant was observed in the following populations: African in 3 of 24974 chromosomes (freq: 0.0001), East Asian in 3 of 19954 chromosomes (freq: 0.0002), Other in 2 of 7228 chromosomes (freq: 0.0003), Latino in 1 of 35440 chromosomes (freq: 0.00003). The variant was not observed in the Ashkenazi Jewish, European (Finnish or non-Finnish), and South Asian populations. The p.Thr470Ile variant did not segregate with diffuse gastric carcinoma in one family studied; in addition the variant co-occurred in trans with another frameshift CDH1 variant that was most likely responsible for the diffuse gastric cancers in this family (Guilford, 1998). The p.Thr470Ile variant was identified in dbSNP (ID: rs370864592) as "With other allele", ClinVar (Clinical Significance: Benign – called by ClinGen expert panel, Invitae, Quest Diagnostics and Integrated Genetics; called likely benign by GeneDx and four other submitters; called VUS by Knight Diagnostic Laboratory). The p.Thr470 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; nevertheless, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001705821	SCV001934567	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-09-03	no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115841	SCV001977038	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-27	no assertion criteria provided	clinical testing