Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000525737 | SCV000637781 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 740 of the CDH1 protein (p.Pro740Ser). This variant is present in population databases (rs773795943, gnomAD 0.006%). 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: 463748). 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. |
| Ambry Genetics | RCV000567386 | SCV000669057 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-11-16 | criteria provided, single submitter | clinical testing | The p.P740S variant (also known as c.2218C>T), located in coding exon 14 of the CDH1 gene, results from a C to T substitution at nucleotide position 2218. The proline at codon 740 is replaced by serine, an amino acid with similar properties. This alteration was observed with an allele frequency of 0.0000 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00018 in 11,241 female controls of Japanese ancestry. In addition, it was observed with an allele frequency of 0.0000 in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0003 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is highly 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000586796 | SCV000698380 | uncertain significance | not provided | 2016-07-01 | criteria provided, single submitter | clinical testing | Variant summary: The CDH1 c.2218C>T (p.Pro740Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SC35. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/121412 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283). Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. |
| Color Diagnostics, |
RCV000567386 | SCV000908758 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-04-19 | criteria provided, single submitter | clinical testing | |
| Cancer Genomics Group, |
RCV001030614 | SCV001193548 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2019-05-01 | criteria provided, single submitter | research | |
| Gene |
RCV000586796 | SCV002007438 | uncertain significance | not provided | 2019-12-24 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not detected in any female or male cases in a breast cancer study, but was detected in the unaffected controls (Momozawa 2018); This variant is associated with the following publications: (PMID: 29338689, 30287823, 29936259) |
| Baylor Genetics | RCV004568802 | SCV005060072 | uncertain significance | Familial cancer of breast | 2024-02-25 | criteria provided, single submitter | clinical testing |