Submissions for variant NM_004360.5(CDH1):c.2520C>T (p.Ser840=)

gnomAD frequency: 0.00064  dbSNP: rs140328601

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212389	SCV000210887	benign	not specified	2014-08-22	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.
Ambry Genetics	RCV000160378	SCV000212814	likely benign	Hereditary cancer-predisposing syndrome	2014-06-19	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.
Invitae	RCV000989627	SCV000252793	benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160378	SCV000684439	benign	Hereditary cancer-predisposing syndrome	2015-04-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586059	SCV000698388	benign	not provided	2016-05-03	criteria provided, single submitter	clinical testing	Variant summary: The c.2520C>T variant affects a non-conserved nucleotide, resulting in a synonymous change. 5/5 in silico tools via Alamut predict no significant effect on splicing. This variant is found in 40/121410 control chromosomes at a frequency of 0.0003295, which is about 12 times of the maximal expected frequency of a pathogenic allele (0.0000283), suggesting this variant is benign. In addition, multiple reputable clinical laboratories have classified this variant as benign/likely benign. Taken together, this variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212389	SCV000889255	benign	not specified	2021-12-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000989627	SCV001140156	likely benign	Hereditary diffuse gastric adenocarcinoma	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798550	SCV002043276	likely benign	Breast and/or ovarian cancer	2019-05-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212389	SCV002069518	likely benign	not specified	2021-06-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160378	SCV002529149	benign	Hereditary cancer-predisposing syndrome	2021-03-22	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212389	SCV002551804	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	RCV000989627	SCV003926961	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS1; BP4; BP7 (PMID: 30311375)
PreventionGenetics, part of Exact Sciences	RCV003927526	SCV004746074	likely benign	CDH1-related condition	2023-05-12	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Mayo Clinic Laboratories, Mayo Clinic	RCV000212389	SCV000691832	likely benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000989627	SCV001548790	likely benign	Hereditary diffuse gastric adenocarcinoma		no assertion criteria provided	clinical testing	The CDH1 p.Ser840= variant was identified in 5 of 558 proband chromosomes (frequency: 0.009) from Spanish and Brazilian individuals or families with nonsyndromic orofacial cleft or MSH2-deficient Lynch syndrome, and was present in 2 of 1218 control chromosomes (frequency: 0.002) from healthy individuals (Brito 2015, Vargas-Parra 2017). The variant was identified in 1 proband whose two colorectal tumors showed coexistence of double somatic mutations and completely different MSI profiles: the MSI tumor (cancer 1) mainly harbored deletions at homopolymeric sequences, whereas the MSS tumor (cancer 2) harbored substitutions (Vargas-Parra 2017). The variant was identified in dbSNP (ID: rs140328601) “With Likely benign allele”, ClinVar (classified benign by GeneDx and Invitae, and likely benign by Ambry Genetics), Clinvitae (3x), LOVD 3.0 (2x), and in control databases in 105 of 277240 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 42 of 24040 chromosomes (freq: 0.002), Other in 5 of 6466 chromosomes (freq: 0.0008), Latino in 37 of 34418 chromosomes (freq: 0.001), European Non-Finnish in 21 of 126722 chromosomes (freq: 0.0002); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant was not identified in Cosmic, MutDB, and Zhejiang Colon Cancer Database. The p.Ser840= 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. This variant was identified in our laboratory with a co-occurring pathogenic BRCA2 variant (c.3455T>G, p.Leu1152*) in the context of early onset TNBC, increasing the likelihood that the c.2520C>T variant does not have clinical significance. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000586059	SCV001743829	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000586059	SCV001807396	likely benign	not provided		no assertion criteria provided	clinical testing