Submissions for variant NM_004360.5(CDH1):c.1308G>A (p.Leu436=)

dbSNP: rs557551011

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123234	SCV000166540	benign	Hereditary diffuse gastric adenocarcinoma	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163855	SCV000214441	likely benign	Hereditary cancer-predisposing syndrome	2014-09-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Illumina Laboratory Services, Illumina	RCV000123234	SCV000398564	benign	Hereditary diffuse gastric adenocarcinoma	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Counsyl	RCV000123234	SCV000488579	likely benign	Hereditary diffuse gastric adenocarcinoma	2016-05-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163855	SCV000684351	benign	Hereditary cancer-predisposing syndrome	2016-07-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755901	SCV000883550	benign	not provided	2018-04-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000755901	SCV000889246	benign	not provided	2022-10-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193902	SCV001363068	benign	not specified	2019-11-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000755901	SCV001836496	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798405	SCV002043251	likely benign	Breast and/or ovarian cancer	2019-10-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163855	SCV002529055	benign	Hereditary cancer-predisposing syndrome	2021-06-27	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193902	SCV002760858	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315820	SCV004017001	benign	Malignant tumor of prostate	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000123234	SCV004019994	benign	Hereditary diffuse gastric adenocarcinoma	2023-03-06	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.
CeGaT Center for Human Genetics Tuebingen	RCV000755901	SCV004140030	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	CDH1: BP4, BP7, BS1
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001193902	SCV001548741	benign	not specified		no assertion criteria provided	clinical testing	The CDH1 p.Leu436= variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs557551011) as “With other allele” and ClinVar (classified benign by Invitae, Color, ARUP and Quest Diagnostics Nichols Institute San Juan Capistrano; and as likely benign by Ambry Genetics, Illumina and Counsyl). The variant was identified in control databases in 75 (2 homozygous) of 246250 chromosomes at a frequency of 0.0003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5486 chromosomes (freq: 0.0002), Latino in 2 of 33582 chromosomes (freq: 0.00006), European Non-Finnish in 1 of 111698 chromosomes (freq: 0.000009), and South Asian in 71 (2 homozygous) of 30782 chromosomes (freq: 0.002), while it was not observed in the African, Ashkenazi Jewish, East Asian or European Finnish populations. The p.Leu436= 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. In addition, 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.