Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000559657 | SCV000637718 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2017-03-02 | criteria provided, single submitter | clinical testing | This sequence change replaces serine with glycine at codon 5 of the CDH1 protein (p.Ser5Gly). The serine residue is weakly conserved and there is a small physicochemical difference between serine and glycine. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. 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, but these predictions have not been confirmed by published functional studies. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a CDH1-related disease. |
| Ambry Genetics | RCV002395361 | SCV002697718 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-23 | criteria provided, single submitter | clinical testing | The p.S5G variant (also known as c.13A>G), located in coding exon 1 of the CDH1 gene, results from an A to G substitution at nucleotide position 13. The serine at codon 5 is replaced by glycine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 4400 samples (8800 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 105,000 alleles tested) in our clinical cohort. This amino acid position is poorly 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 p.S5G remains unclear. |
| Laboratorio de Genetica e Diagnostico Molecular, |
RCV000559657 | SCV003807626 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2022-10-14 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PM2 moderated, BP4 supporting |