Submissions for variant NM_004360.5(CDH1):c.2080G>A (p.Val694Ile)

dbSNP: rs587780118

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115849	SCV000149758	uncertain significance	not provided	2023-05-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30287823, 15235021, 22850631, 24690483, 32175104)
Ambry Genetics	RCV000222804	SCV000273443	likely benign	Hereditary cancer-predisposing syndrome	2017-02-01	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.
Invitae	RCV000530518	SCV000637770	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 694 of the CDH1 protein (p.Val694Ile). This variant is present in population databases (rs587780118, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of CDH1-related conditions (PMID: 36436516). ClinVar contains an entry for this variant (Variation ID: 127920). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000222804	SCV000684394	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-16	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 694 of the CDH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251380 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
MGZ Medical Genetics Center	RCV002288600	SCV002581459	uncertain significance	Familial cancer of breast	2022-02-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509224	SCV002819269	uncertain significance	not specified	2022-12-05	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2080G>A (p.Val694Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251380 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.2080G>A has not been observed in individuals affected with Hereditary Diffuse Gastric Cancer or other hereditary cancers, and no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000530518	SCV003926888	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2; BS2_Supporting (PMID: 30311375)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002509224	SCV004026650	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115849	SCV004220814	uncertain significance	not provided	2022-09-22	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251380 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a somatic variant in gastric tumor tissue (PMIDs: 24690483 (2014) and 26486520 (2015)). Additionally, the variant has been seen in individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CDH1)) and unaffected individuals (PMIDs: 30287823 (2018) and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CDH1). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.