Submissions for variant NM_004360.5(CDH1):c.304G>T (p.Ala102Ser)

dbSNP: rs368492235

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167482	SCV000218339	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	The p.A102S variant (also known as c.304G>T), located in coding exon 3 of the CDH1 gene, results from a G to T substitution at nucleotide position 304. The alanine at codon 102 is replaced by serine, an amino acid with similar properties. This amino acid position is 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.
GeneDx	RCV000479588	SCV000567588	uncertain significance	not provided	2015-08-07	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.304G>T at the cDNA level, p.Ala102Ser (A102S) at the protein level, and results in the change of an Alanine to a Serine (GCC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 Ala102Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Alanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Ala102Ser occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether CDH1 Ala102Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000639246	SCV000760816	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 102 of the CDH1 protein (p.Ala102Ser). This variant is present in population databases (rs368492235, gnomAD 0.002%). 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: 187729). 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 serine 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	RCV000167482	SCV001734425	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 102 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 identified in 2/251274 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.
Genetic Services Laboratory, University of Chicago	RCV001818399	SCV002068582	uncertain significance	not specified	2019-02-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000479588	SCV004026189	uncertain significance	not provided	2021-07-20	criteria provided, single submitter	clinical testing	PM2_SUP
Baylor Genetics	RCV003462244	SCV004215617	uncertain significance	Familial cancer of breast	2023-10-09	criteria provided, single submitter	clinical testing