Submissions for variant NM_004360.5(CDH1):c.1603A>C (p.Ile535Leu)

dbSNP: rs144519845

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000569091	SCV000669046	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-03	criteria provided, single submitter	clinical testing	The p.I535L variant (also known as c.1603A>C), located in coding exon 11 of the CDH1 gene, results from an A to C substitution at nucleotide position 1603. The isoleucine at codon 535 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000569091	SCV000684367	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 535 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 CDH1-related disorders in the literature. This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001230769	SCV001403262	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-07-25	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 535 of the CDH1 protein (p.Ile535Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 483246). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx	RCV004722934	SCV005332822	uncertain significance	not provided	2024-01-05	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: 15235021, 22850631)
PreventionGenetics, part of Exact Sciences	RCV004722935	SCV005337211	uncertain significance	CDH1-related disorder	2024-08-05	no assertion criteria provided	clinical testing	The CDH1 c.1603A>C variant is predicted to result in the amino acid substitution p.Ile535Leu. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant has an interpretation of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/483246/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.