ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.33G>C (p.Leu11=)

gnomAD frequency: 0.00019  dbSNP: rs730881654
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000199871 SCV001142256 likely benign Hereditary diffuse gastric adenocarcinoma 2019-06-18 reviewed by expert panel curation The c.33G>C (p.Leu11=) variant results in a synonymous amino acid variant within exon 1. This variant is present at an allele frequency of 0.00012 (18/153328) in gnomAD, with a maximum frequency of 0.00026 (16/60398) in the European (Non-Finnish) subpopulation (http://gnomad.broadinstitute.org). The variant has been observed in more than 10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; unpublished). This variant occurs at a nucleotide that is not highly conserved across species and it is not predicted to alter splicing by multiple splice site predictors (BP7, BP4). Although one predictor suggests alteration of an exonic ESE site, the impact of these events has not been well-characterized experimentally. In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2, BP4, BP7.
GeneDx RCV000212344 SCV000210878 benign not specified 2014-08-25 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 RCV000160369 SCV000213221 likely benign Hereditary cancer-predisposing syndrome 2014-08-29 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 RCV000199871 SCV000253423 likely benign Hereditary diffuse gastric adenocarcinoma 2021-12-17 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000199871 SCV000398544 uncertain significance Hereditary diffuse gastric adenocarcinoma 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health RCV000160369 SCV000537422 likely benign Hereditary cancer-predisposing syndrome 2015-07-27 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000212344 SCV000593910 likely benign not specified 2017-01-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212344 SCV000600985 likely benign not specified 2016-06-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212344 SCV000698396 benign not specified 2018-01-02 criteria provided, single submitter clinical testing Variant summary: The CDH1 c.33G>C (p.Leu11Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 18/153328 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000265 (16/60398). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
PreventionGenetics,PreventionGenetics RCV000589980 SCV000806665 likely benign not provided 2017-11-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589980 SCV000889258 benign not provided 2017-08-03 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000589980 SCV002047788 likely benign not provided 2020-10-09 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000160369 SCV002529173 benign Hereditary cancer-predisposing syndrome 2021-03-19 criteria provided, single submitter curation
Mayo Clinic Laboratories,Mayo Clinic RCV000212344 SCV000691808 likely benign not specified no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000199871 SCV001551171 likely benign Hereditary diffuse gastric adenocarcinoma no assertion criteria provided clinical testing The CDH1 p.Leu11= variant was not identified in the literature nor was it identified in the MutDB or Zhejiang University databases. The variant was identified in dbSNP (ID: rs730881654 as "With other allele") and ClinVar (1x as benign by GeneDx; 6x as likely benign by Ambry Genetics, Invitae, Color Genomics, and three other clinical laboratories; and 2x as uncertain significance by Integrated Genetics/Laboratory Corporation of America). The variant was identified in control databases in 18 of 153328 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 13794 chromosomes (freq: 0.00007), Other in 1 of 4418 chromosomes (freq: 0.0002), and European in 16 of 60398 chromosomes (freq: 0.0003), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu11= 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. The variant occurs outside of the splicing consensus sequence and only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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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