Submissions for variant NM_004360.5(CDH1):c.2046G>A (p.Glu682=)

gnomAD frequency: 0.00001  dbSNP: rs753209043

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163655	SCV000214225	likely benign	Hereditary cancer-predisposing syndrome	2014-09-04	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203789	SCV000259392	likely benign	Hereditary diffuse gastric adenocarcinoma	2025-01-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163655	SCV000684391	likely benign	Hereditary cancer-predisposing syndrome	2016-08-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001721050	SCV000729230	likely benign	not provided	2019-12-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000614568	SCV001363069	likely benign	not specified	2019-10-31	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003316003	SCV004017023	likely benign	Malignant tumor of prostate	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000614568	SCV004026649	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000203789	SCV005404186	benign	Hereditary diffuse gastric adenocarcinoma	2024-09-20	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354598	SCV001549248	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Glu682= variant was not identified in the literature nor was it identified in the Cosmic or Zhejiang University databases. The variant was also identified in dbSNP (ID: rs753209043) as "With Likely benign allele", and in ClinVar (classified as likely benign by Invitae, Ambry Genetics, Color and GeneDx). The variant was identified in control databases in 2 of 246254 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 2 of 111712 chromosomes (freq: 0.00002); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Glu682= 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 but 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.