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

gnomAD frequency: 0.00006  dbSNP: rs145430811

Total submissions: 14

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: 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	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)
Myriad Genetics, Inc.	RCV000989619	SCV005405323	benign	Hereditary diffuse gastric adenocarcinoma	2024-09-12	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
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.