ClinVar Miner

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

gnomAD frequency: 0.00064  dbSNP: rs140328601
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Total submissions: 15
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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 2021-12-17 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 RCV000586059 SCV000889255 benign not provided 2017-10-02 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
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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000212389 SCV002551804 likely benign not specified 2021-10-08 no assertion criteria provided clinical testing

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