Submissions for variant NM_004360.5(CDH1):c.84C>T (p.Cys28=)

gnomAD frequency: 0.00004  dbSNP: rs587780789

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079933	SCV000166562	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163675	SCV000214248	likely benign	Hereditary cancer-predisposing syndrome	2014-10-31	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.
Color Diagnostics, LLC DBA Color Health	RCV000163675	SCV000537461	likely benign	Hereditary cancer-predisposing syndrome	2015-08-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000614020	SCV000714356	benign	not specified	2015-07-01	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757067	SCV000885156	likely benign	not provided	2018-03-28	criteria provided, single submitter	clinical testing	The CDH1 c.84C>T; p.Cys28Cys variant (rs587780789), to our knowledge, is not reported in the medical literature but is reported as likely benign in ClinVar (Variation ID: 136070). This variant is found in the general population with an overall allele frequency of 0.003% (4/149530 alleles) in the Genome Aggregation Database. This is a synonymous change, the nucleotide is weakly conserved, and computational algorithms do not predict this variant to impact splicing (Alamut v.2.10). Based on available information, this variant is considered to be likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000614020	SCV000919102	likely benign	not specified	2018-03-16	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.84C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.00e-05 within Non-Finnish European control individuals (i.e. 4/57386 control chromosomes) in the gnomAD database, which is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.84C>T in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000614020	SCV002551739	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505074	SCV002804832	likely benign	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2021-12-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001079933	SCV005403867	benign	Hereditary diffuse gastric adenocarcinoma	2024-09-11	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.