Submissions for variant NM_004360.5(CDH1):c.1896C>T (p.His632=)

gnomAD frequency: 0.02054  dbSNP: rs33969373

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328211	SCV001365420	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-10	reviewed by expert panel	curation	The NM_004360.5(CDH1):c.1896C>T (p.His632=) variant has an allele frequency of 0.05030 (5%, 1255/24950 alleles, 32 homozygotes) in the African subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, 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): BA1, BP2.
Ambry Genetics	RCV000130151	SCV000184986	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
PreventionGenetics, part of Exact Sciences	RCV000249039	SCV000310123	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000287503	SCV000398572	benign	Hereditary diffuse gastric adenocarcinoma	2018-01-13	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.
Color Diagnostics, LLC DBA Color Health	RCV000130151	SCV000537367	benign	Hereditary cancer-predisposing syndrome	2015-04-02	criteria provided, single submitter	clinical testing
Invitae	RCV000287503	SCV000557383	benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705928	SCV000883548	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001705928	SCV001912269	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000249039	SCV002551785	benign	not specified	2023-08-15	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	RCV000287503	SCV003926866	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BA1; BP2_Strong (PMID: 30311375)
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315887	SCV004016998	benign	Malignant tumor of prostate	2023-07-07	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000130151	SCV000787979	likely benign	Hereditary cancer-predisposing syndrome	2017-11-15	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355823	SCV001550820	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.His632= variant was identified in 7 of 716 proband chromosomes (frequency: 0.010) from Polish, Italian and multiethnic cohorts of individuals or families with hereditary diffuse gastric cancer, nonhereditary or at risk gastric cancer and breast cancer (invasive lobular carcinoma), and was present in 7 of 304 control chromosomes (frequency: 0.02) from healthy individuals (Jakubowska 2010, Oliveira 2002, Valente 2014 , Garziera 2013). In one study, individuals found to carry the variant were those at risk of gastric cancer but not with sporadic gastric cancer (Garziera 2013). The variant has been reported as a polymorphism (frequency unspecified), in several studies (Berx 1997, Gayther 1998). The variant was identified in dbSNP (ID: rs33969373) “With Benign allele”, ClinVar database (classification benign by Ambry Genetics, Prevention Genetics, Illumina, Color Genomics and Invitae), Clinvitae (3X classified as benign), Cosmic (2X in a haemangioblastoma and thyroid tumor), and the Zhejiang Colon Cancer Database (3X); and was not identified in MutDB, or Insight Colon Cancer Gene Variant Database. The variant was also identified in control databases in 3105 (57 homozygous) of 277164 chromosomes at a frequency of 0.0112, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27 2017); being identified in the following populations at a frequency greater than 1%: African in 1191 of 24012 chromosome (freq: 0.05), Other in 128 of 6464 chromosomes (freq. 0.02), Latino in 477 of 34418 chromosomes (freq. 0.014), and in Ashkenazi Jewish in 103 of 10152 chromosomes (freq. 0.010). The p.His632His 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, HumanSpliceFinder) 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000249039	SCV001809251	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000249039	SCV001906012	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000249039	SCV001923994	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000249039	SCV001959791	benign	not specified		no assertion criteria provided	clinical testing