Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003328427 | SCV004035082 | uncertain significance | CDH1-related diffuse gastric and lobular breast cancer syndrome | 2023-08-02 | reviewed by expert panel | curation | The c.112A>C (NM_004360.5) variant in CDH1 is a missense variant predicted to cause substitution in exon 2 (p.Thr38Pro). This variant was observed in seven individuals with no DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2_Supporting; Invitae). Note that this includes two individuals with a family history of stomach cancer NOS. This variant is absent from gnomAD 2.1.1 (PM2_Spporting). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2_supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023) |
| Color Diagnostics, |
RCV000579397 | SCV000684328 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-02-04 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with proline at codon 38 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 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. |
| Labcorp Genetics |
RCV000686759 | SCV000814292 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2023-09-17 | criteria provided, single submitter | clinical testing | 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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 489846). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 38 of the CDH1 protein (p.Thr38Pro). |
| Ambry Genetics | RCV000579397 | SCV002607872 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-04 | criteria provided, single submitter | clinical testing | The p.T38P variant (also known as c.112A>C), located in coding exon 2 of the CDH1 gene, results from an A to C substitution at nucleotide position 112. The threonine at codon 38 is replaced by proline, 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. |
| Baylor Genetics | RCV003459427 | SCV004215649 | uncertain significance | Familial cancer of breast | 2023-09-06 | criteria provided, single submitter | clinical testing |