Submissions for variant NM_004360.5(CDH1):c.1170CGT[1] (p.Val392del)

dbSNP: rs1555515872

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564644	SCV000665129	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-31	criteria provided, single submitter	clinical testing	The c.1173_1175delCGT variant (also known as p.V392del) is located in coding exon 9 of the CDH1 gene. This variant results from an in-frame CGT deletion at nucleotide positions 1173 to 1175. This results in the in-frame deletion of a valine at codon 392. The deleted amino acid position is poorly conserved in available vertebrate species. However, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697960	SCV000826595	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-08-10	criteria provided, single submitter	clinical testing	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: 481037). This variant is not present in population databases (gnomAD no frequency). This variant, c.1173_1175del, results in the deletion of 1 amino acid(s) of the CDH1 protein (p.Val392del), but otherwise preserves the integrity of the reading frame. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357435	SCV001552906	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Val392del variant was not identified in the literature nor was it identified in the dbSNP database. The variant was identified in ClinVar (interpreted as "uncertain significance" by Invitae and Ambry Genetics). The variant was not identified in the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame deletion resulting in the removal of a valine (Val) residue at codon 392; the impact of this alteration on CDH1 protein function is not known. Two out of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.