Submissions for variant NM_004360.5(CDH1):c.1876T>G (p.Phe626Val)

dbSNP: rs876660603

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215202	SCV000278164	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-20	criteria provided, single submitter	clinical testing	The p.F626V variant (also known as c.1876T>G), located in coding exon 12 of the CDH1 gene, results from a T to G substitution at nucleotide position 1876. The phenylalanine at codon 626 is replaced by valine, an amino acid with highly similar properties. In one study, this variant was reported in both an infiltrating lobular breast tumor and normal tissue from one patient (Sarrió D et al. Int. J. Cancer 2003 Aug; 106(2):208-15). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456373	SCV000545382	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 626 of the CDH1 protein (p.Phe626Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with lobular breast cancer (PMID: 12800196). ClinVar contains an entry for this variant (Variation ID: 233729). 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.
Color Diagnostics, LLC DBA Color Health	RCV000215202	SCV001356360	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-18	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with valine at codon 626 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individuals affected with lobular breast cancer in the literature (PMID 12800196). 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.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000456373	SCV003926864	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2; BP2_Supporting (PMID: 30311375)
Baylor Genetics	RCV004567653	SCV005060066	uncertain significance	Familial cancer of breast	2024-03-03	criteria provided, single submitter	clinical testing