Submissions for variant NM_004360.5(CDH1):c.1171G>T (p.Val391Phe)

dbSNP: rs556110297

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160389	SCV000210907	uncertain significance	not provided	2014-06-27	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.1171G>T at the cDNA level, p.Val391Phe (V391F) at the protein level, and results in the change of a Valine to a Phenylalanine (GTC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 Val391Phe 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 Valine and Phenylalanine differ in some properties, this is considered a semi-conservative amino acid substitution. CDH1 Val391Phe occurs at a position that is variable across species and is located in the 3rd cadherin repeat (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether CDH1 Val391Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850262	SCV002217021	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2021-04-06	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 182396). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with phenylalanine at codon 391 of the CDH1 protein (p.Val391Phe). The valine residue is weakly conserved and there is a small physicochemical difference between valine and phenylalanine.