Submissions for variant NM_004360.5(CDH1):c.896C>G (p.Ala299Gly)

gnomAD frequency: 0.00001  dbSNP: rs745807727

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231332	SCV000288500	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 299 of the CDH1 protein (p.Ala299Gly). This variant is present in population databases (rs745807727, gnomAD 0.002%). 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: 239916). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
GeneDx	RCV000479514	SCV000572898	uncertain significance	not provided	2023-07-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal and/or family history of breast cancer (Garcia-Pelaez et al., 2023); This variant is associated with the following publications: (PMID: 15235021, 22850631, 36436516)
Color Diagnostics, LLC DBA Color Health	RCV000580494	SCV000684493	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-24	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 299 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/282880 chromosomes 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	RCV000231332	SCV003926702	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	Not applicable criteria (PMID: 30311375)
Ambry Genetics	RCV000580494	SCV005022442	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	The p.A299G variant (also known as c.896C>G), located in coding exon 7 of the CDH1 gene, results from a C to G substitution at nucleotide position 896. The alanine at codon 299 is replaced by glycine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with breast cancer (Garcia-Pelaez J et al. Lancet Oncol, 2023 Jan;24:91-106). This amino acid position is not 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.