Submissions for variant NM_004360.5(CDH1):c.2440-6C>G

gnomAD frequency: 0.00145  dbSNP: rs139757930

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000417376	SCV000149764	benign	not specified	2017-05-01	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123249	SCV000166555	benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115855	SCV000185892	likely benign	Hereditary cancer-predisposing syndrome	2021-11-04	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.
Illumina Laboratory Services, Illumina	RCV000123249	SCV000398582	likely benign	Hereditary diffuse gastric adenocarcinoma	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115855	SCV000684435	likely benign	Hereditary cancer-predisposing syndrome	2015-01-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590568	SCV000698385	benign	not provided	2016-01-25	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a non-conserved intronic nucleotide located at a position not widely known to affect splicing. Mutation taster predicts the variant to be neutral along with 5/5 in silico tools via Alamut predicting no significant effect on normal splicing by the variant. The variant was in the large and broad cohorts of the ExAC project at an allele frequency of o,1% which is 63 times higher than the maximal expected allele frequency of a disease causing CDH1 allele (0.0028%) indicating a neutral impact. The variant showed lack of co-segregation with HDGC in one family (Grodecka_GCC_2014) and was shown not to affect splicing and the expression level of the protein (Grodecka_GCC_2014; Molinaro_GCC_2014) further supporting a benign nature. Additionally, clinical diagnostic centers classify variant as Likely Benign/Benign (without evidence to independently evaluate). Considering all evidence, the variant was classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000417376	SCV000806661	benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000123249	SCV000839099	likely benign	Hereditary diffuse gastric adenocarcinoma	2018-07-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590568	SCV001150959	benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	CDH1: BP4, BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590568	SCV001471512	benign	not provided	2023-09-08	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798347	SCV002043273	benign	Breast and/or ovarian cancer	2019-05-24	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000417376	SCV002066677	benign	not specified	2020-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115855	SCV002529139	benign	Hereditary cancer-predisposing syndrome	2020-09-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000417376	SCV002551803	likely 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	RCV000123249	SCV003926951	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS1; BS2; BS3; BP4 (PMID: 30311375)
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315642	SCV004017014	benign	Malignant tumor of prostate	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000590568	SCV005219066	likely benign	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV000417376	SCV000691831	benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000115855	SCV000787983	benign	Hereditary cancer-predisposing syndrome	2017-11-15	no assertion criteria provided	clinical testing
King Laboratory, University of Washington	RCV000417376	SCV001251332	benign	not specified	2019-09-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357289	SCV001552715	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 c.2440-6C>G variant was identified in 3 of 462 proband chromosomes (frequency: 0.006) from individuals or families with diffuse gastric and lung cancer (Guilford 2007, More 2007, Yorczyk 2015). The variant was also identified in the following databases: dbSNP (ID: rs139757930) as With Likely benign, ClinVar (classified as benign by Invitae, as likely benign by GeneDx and Ambry Genetics), Clinvitae (classified as likely benign by ClinVar, Invitae), Insight Colon Cancer Gene Variant Database (1X), and the Zhejiang Colon Cancer Database. The variant was identified in control databases in 453 (1 homozygous) of 277200 chromosomes at a frequency of 0.0016 in the following populations: European in 215 of 126702 chromosomes (freq. 0.002), Latino in 126 of 34420 chromosomes (freq. 0.004), Ashkenazi Jewish in 73 of 10152 chromosomes (freq. 0.007), Other in 29 of 6466 chromosomes (freq. 0.004), South Asian in 6 of 30782 chromosomes (freq.0.0002), African in 4 of 24024 chromosomes (freq. 0.0002), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The c.2440-6C>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. There is conflicting evidence in the literature regarding effect on splicing. The variant causes abnormal RNA transcripts compared to RNA from a healthy unrelated control Individuals in More et al. (2007), while in Grodeck√° (2014) results showed mostly correctly spliced transcripts of both wild type and c.2440-6C>G variants. 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000590568	SCV001809699	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000590568	SCV001925906	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000417376	SCV001930843	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590568	SCV001954836	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000590568	SCV001966127	likely benign	not provided		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115855	SCV002050292	likely benign	Hereditary cancer-predisposing syndrome	2021-10-27	no assertion criteria provided	clinical testing