Submissions for variant NM_004360.5(CDH1):c.2033T>C (p.Val678Ala)

gnomAD frequency: 0.00001  dbSNP: rs876659352

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218033	SCV000275723	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	The p.V678A variant (also known as c.2033T>C), located in coding exon 13 of the CDH1 gene, results from a T to C substitution at nucleotide position 2033. The valine at codon 678 is replaced by alanine, an amino acid with similar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). 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.
Color Diagnostics, LLC DBA Color Health	RCV000218033	SCV000904788	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 678 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 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	RCV001062288	SCV001227077	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 678 of the CDH1 protein (p.Val678Ala). 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: 231773). 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.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV001062288	SCV003926883	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2 (PMID: 30311375)