Submissions for variant NM_004360.5(CDH1):c.2558C>T (p.Ser853Leu)

gnomAD frequency: 0.00002  dbSNP: rs569928380

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165032	SCV000215729	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-20	criteria provided, single submitter	clinical testing	The p.S853L variant (also known as c.2558C>T), located in coding exon 16 of the CDH1 gene, results from a C to T substitution at nucleotide position 2558. The serine at codon 853 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a Spanish cohort of patients from clinically suspicious hereditary breast and/or ovarian cancer families without BRCA1/2 mutations (Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513). This alteration has also been reported as a germline finding in a patient from a Hispanic/Latino gastric cancer cohort (Wang SC et al. Cancer Res, 2020 06;80:2114-2124). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466545	SCV000545469	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 853 of the CDH1 protein (p.Ser853Leu). This variant is present in population databases (rs569928380, gnomAD 0.009%). This missense change has been observed in individual(s) with diffuse gastric cancer and/or ovarian cancer (PMID: 30306255, 32269045). ClinVar contains an entry for this variant (Variation ID: 185587). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV000165032	SCV000684440	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 853 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been reported in individuals with ovarian cancer (PMID: 30306255), gastric cancer (PMID: 32269045) and breast cancer (PMID: 33471991), but has also been observed in unaffected individuals (PMID: 33471991). This variant has been identified in 4/251482 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759731	SCV000889256	uncertain significance	not provided	2023-08-31	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 30306255 (2018)), gastric cancer (PMID: 32269045 (2020)), breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CDH1)), and other unspecified cancers (PMID: 36436516 (2023)). This variant is also reported in an unaffected individual (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CDH1)). The frequency of this variant in the general population, 0.000087 (3/34590 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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.
GeneDx	RCV000759731	SCV001813159	uncertain significance	not provided	2021-05-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with diffuse gastric cancer or ovarian cancer (Bonache 2018, Wang 2020); This variant is associated with the following publications: (PMID: 30306255, 32269045)
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000466545	SCV003926964	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	Not applicable criteria (PMID: 30311375)
Baylor Genetics	RCV004567259	SCV005060084	uncertain significance	Familial cancer of breast	2024-02-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016494	SCV005644360	uncertain significance	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian cancer	2024-06-21	criteria provided, single submitter	clinical testing