Submissions for variant NM_004360.5(CDH1):c.1353T>C (p.Ile451=)

gnomAD frequency: 0.00014  dbSNP: rs114192597

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212368	SCV000167594	benign	not specified	2014-05-09	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	RCV000124180	SCV000213199	likely benign	Hereditary cancer-predisposing syndrome	2014-07-28	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.
Invitae	RCV001082608	SCV000253408	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212368	SCV000600958	benign	not specified	2017-06-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000124180	SCV000684355	likely benign	Hereditary cancer-predisposing syndrome	2015-08-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588656	SCV000698361	benign	not provided	2017-06-05	criteria provided, single submitter	clinical testing	Variant summary: The CDH1 c.1353T>C (p.Ile451Ile) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a disease-causing outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 10/121402 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.00015 (10/66738). This frequency is about 5 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 European (Non-Finnish) origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
Sema4, Sema4	RCV000124180	SCV002529058	likely benign	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492567	SCV004240420	likely benign	Breast and/or ovarian cancer	2022-08-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003915242	SCV004728157	likely benign	CDH1-related disorder	2019-03-12	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Mayo Clinic Laboratories, Mayo Clinic	RCV000212368	SCV000691820	likely benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356276	SCV001551398	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Ile451= variant was not identified in the literature nor was it identified in the Cosmic, or Zhejiang University databases. The variant was identified in dbSNP (ID: rs114192597) as "With Likely benign allele", ClinVar (classified as benign by GeneDx, Quest Diagnostics Nichols Institute San Juan Capistrano and Integrated Genetics/Laboratory Corporation of America; as likely benign by Ambry genetics, Invitae, Color Genomics), and Clinvitae databases. The variant was identified in control databases in 22 of 277240 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 24040 chromosomes (freq: 0.00004), Latino in 1 of 34420 chromosomes (freq: 0.00003), and European in 20 of 126716 chromosomes (freq: 0.0002), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ile451= 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. 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 greater than 10% 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.