ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.393C>T (p.Ser131=)

gnomAD frequency: 0.00006  dbSNP: rs145430811
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163207 SCV000213730 likely benign Hereditary cancer-predisposing syndrome 2014-06-30 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 RCV000989619 SCV000259850 likely benign Hereditary diffuse gastric adenocarcinoma 2024-01-09 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000163207 SCV000684459 likely benign Hereditary cancer-predisposing syndrome 2016-02-17 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV000679575 SCV000806669 likely benign not provided 2017-12-28 criteria provided, single submitter clinical testing
Mendelics RCV000989619 SCV001140132 likely benign Hereditary diffuse gastric adenocarcinoma 2019-05-28 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000989619 SCV001279850 likely benign Hereditary diffuse gastric adenocarcinoma 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194006 SCV001363229 benign not specified 2019-03-28 criteria provided, single submitter clinical testing Variant summary: CDH1 c.393C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0001 in 277130 control chromosomes. The observed variant frequency is approximately 3.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.393C>T in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx RCV000679575 SCV001945445 benign not provided 2015-03-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679575 SCV002047265 benign not provided 2021-05-03 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000163207 SCV002529181 benign Hereditary cancer-predisposing syndrome 2021-12-21 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001194006 SCV002551751 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 RCV000989619 SCV003927042 likely benign Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PS4_Supporting; BP4; BP7 (PMID: 30311375)
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000989619 SCV001552495 likely benign Hereditary diffuse gastric adenocarcinoma no assertion criteria provided clinical testing The CDH1 p.Ser131= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs145430811) as "With Likely benign allele", and in ClinVar (classified as likely benign by Invitae, Ambry Genetics, Color and Prevention Genetics). The variant was identified in 29 of 277130 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 28 of 126628 chromosomes (freq: 0.0002), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Ser131= 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 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.

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