Submissions for variant NM_004360.5(CDH1):c.894C>T (p.Ala298=)

gnomAD frequency: 0.00009  dbSNP: rs139110184

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162667	SCV000213114	likely benign	Hereditary cancer-predisposing syndrome	2014-08-21	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	RCV001083994	SCV000253429	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000417807	SCV000512514	benign	not specified	2015-09-04	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.
Color Diagnostics, LLC DBA Color Health	RCV000162667	SCV000689572	likely benign	Hereditary cancer-predisposing syndrome	2017-05-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589062	SCV000698413	benign	not provided	2016-11-04	criteria provided, single submitter	clinical testing	Variant summary: The CDH1 c.894C>T (p.Ala298Ala) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts that this variant may affect ESE binding, however, these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 22/121408 (1/5518), which exceeds the estimated maximal expected allele frequency for a pathogenic CDH1 variant of 1/35335, suggesting this variant is likely a benign polymorphism. The variant of interest has been reported in an affected individual, however, with limited information (ie, lack of co-occurrence and cosegregation data) and the authors classify the variant as a "polymorphism." In addition, multiple clinical diagnostic laboratories cite the variant as "likely benign." Therefore, the variant of interest has been classified as Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589062	SCV000888045	benign	not provided	2023-06-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001083994	SCV001274413	benign	Hereditary diffuse gastric adenocarcinoma	2018-03-06	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Sema4, Sema4	RCV000162667	SCV002529222	benign	Hereditary cancer-predisposing syndrome	2021-09-04	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149990	SCV003837768	likely benign	Breast and/or ovarian cancer	2022-12-14	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	RCV001083994	SCV003926701	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BP4; BP7 (PMID: 30311375)
PreventionGenetics, part of Exact Sciences	RCV003937481	SCV004749711	likely benign	CDH1-related condition	2019-05-22	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357570	SCV001553076	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Ala298= variant was identified in 1 of 472 proband chromosomes (frequency: 0.002) from individuals or families with gastric cancer and was not identified in 480 control chromosomes from healthy individuals (Chen 2013). The variant was also identified in dbSNP (ID: rs139110184) as "With Likely benign allele", ClinVar (classified as benign by GeneDx and one other clinical laboratory; classified as likely benign by Ambry Genetics, Invitae, and Color Genomics). The variant was not identified in Cosmic or Zhejiang University Database. The variant was identified in control databases in 39 of 277202 chromosomes at a frequency of 0.00014 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24032 chromosomes (freq: 0.00004), European in 27 of 126700 chromosomes (freq: 0.0002), East Asian in 2 of 18868 chromosomes (freq: 0.0001), Finnish in 9 of 25788 chromosomes (freq: 0.0003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, or South Asian populations. The p.Ala298= 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. 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162667	SCV001950160	likely benign	Hereditary cancer-predisposing syndrome	2021-09-15	no assertion criteria provided	clinical testing