Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003328281 | SCV004035123 | likely benign | CDH1-related diffuse gastric and lobular breast cancer syndrome | 2023-08-02 | reviewed by expert panel | curation | The c.161G>A (p.Arg54Lys) missense variant is absent in the gnomAD 2.1.1 cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been observed in at least 10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000274257.4, SCV000637737.4, unpublished data). In summary, although a conflicting code PM2_supporting is met, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PM2_supporting, BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023) |
| Ambry Genetics | RCV000215888 | SCV000274257 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-04-11 | criteria provided, single submitter | clinical testing | The p.R54K variant (also known as c.161G>A), located in coding exon 2 of the CDH1 gene, results from a G to A substitution at nucleotide position 161. The arginine at codon 54 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is 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. |
| Labcorp Genetics |
RCV000549869 | SCV000637737 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2023-11-03 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 54 of the CDH1 protein (p.Arg54Lys). This variant is not present in population databases (gnomAD no frequency). 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: 230641). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. |
| Sema4, |
RCV000215888 | SCV002529081 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-04-16 | criteria provided, single submitter | curation | |
| Color Diagnostics, |
RCV000215888 | SCV004360434 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-02-14 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with lysine at codon 54 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. |