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

gnomAD frequency: 0.00022  dbSNP: rs730881654

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328242	SCV001142256	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	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). 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 (Variant Interpretation Guidelines Version 3.1): 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	2024-01-31	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
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, part of Exact Sciences	RCV000589980	SCV000806665	likely benign	not provided	2017-11-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212344	SCV000889258	benign	not specified	2022-02-25	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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212344	SCV004026625	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
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.