Submissions for variant NM_004360.5(CDH1):c.1900G>A (p.Ala634Thr)

gnomAD frequency: 0.00001  dbSNP: rs1060501240

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472963	SCV000545450	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-05-27	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Ala634 amino acid residue in CDH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12588804, 17545690; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 406658). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 634 of the CDH1 protein (p.Ala634Thr).
GeneDx	RCV000485862	SCV000566339	uncertain significance	not provided	2015-04-22	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.1900G>A at the cDNA level, p.Ala634Thr (A634T) at the protein level, and results in the change of an Alanine to a Threonine (GCG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 Ala634Thr 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 Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Ala634Thr occurs at a position that is conserved through mammals and is located in the Cadherin 5 and Extracellular domains (UniProt, Figueiredo 2013). 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 Ala634Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001189704	SCV001357053	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 634 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). 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. A different missense variant at this codon, c.1901C>T (p.Ala634Val), is considered disease-causing in ClinVar with reported impact on the variant protein and mRNA splicing (ClinVar variation ID: 12244). However, this variant c.1900G>A (p.Ala634Thr) is not predicted to impact protein function or mRNA splicing. 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.
Ambry Genetics	RCV001189704	SCV002722631	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-22	criteria provided, single submitter	clinical testing	The p.A634T variant (also known as c.1900G>A), located in coding exon 12 of the CDH1 gene, results from a G to A substitution at nucleotide position 1900. The alanine at codon 634 is replaced by threonine, 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.
Baylor Genetics	RCV004567976	SCV005060052	uncertain significance	Familial cancer of breast	2024-03-25	criteria provided, single submitter	clinical testing