ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.387+5G>A

gnomAD frequency: 0.00008  dbSNP: rs113055163
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328225 SCV001437599 benign CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-10 reviewed by expert panel curation The c.387+5G>A variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000329224.7, SCV000288482.5, SCV000186607.5). This variant was also observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer, lobular breast cancer (BP2_Strong; SCV000288482.5). RNA studies demonstrated no abnormal splicing (BS3; PMID: 31642931). In summary, 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): BS2, BS3, BP2_Strong.
Ambry Genetics RCV000131594 SCV000186607 likely benign Hereditary cancer-predisposing syndrome 2018-11-24 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000227422 SCV000288482 benign Hereditary diffuse gastric adenocarcinoma 2024-01-04 criteria provided, single submitter clinical testing
GeneDx RCV000315259 SCV000329224 likely benign not provided 2020-08-25 criteria provided, single submitter clinical testing In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Published functional studies demonstrate no damaging effect: no aberrant splicing observed (Karam 2019); Identified in an individual with nonsyndromic cleft lip and palate (Brito 2015); This variant is associated with the following publications: (PMID: 31638429, 31642931, 30661051, 26123647)
Counsyl RCV000227422 SCV000487845 uncertain significance Hereditary diffuse gastric adenocarcinoma 2015-11-21 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131594 SCV000684457 likely benign Hereditary cancer-predisposing syndrome 2021-07-26 criteria provided, single submitter clinical testing
Mendelics RCV000227422 SCV000839077 benign Hereditary diffuse gastric adenocarcinoma 2023-08-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264448 SCV001442610 likely benign not specified 2020-10-05 criteria provided, single submitter clinical testing Variant summary: CDH1 c.387+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 1.6e-05 in 250142 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.387+5G>A has been reported in the literature in one individual affected with Nonsyndromic Cleft Lip with or without Cleft Palate (Brito_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likelye benign n=2, VUS n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4 RCV000131594 SCV002529178 benign Hereditary cancer-predisposing syndrome 2021-08-17 criteria provided, single submitter curation
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000227422 SCV003927033 benign Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing BS2; BS3; BP2_Strong (PMID: 30311375)
Myriad Genetics, Inc. RCV000227422 SCV004020011 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-03-06 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000315259 SCV004220830 benign not provided 2023-05-11 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001264448 SCV003839327 likely benign not specified 2022-08-22 no assertion criteria provided clinical testing

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