Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000804783 | SCV000944710 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2023-07-17 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 649774). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 505 of the CDH1 protein (p.Ile505Thr). |
| Ambry Genetics | RCV001011874 | SCV001172252 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-12-26 | criteria provided, single submitter | clinical testing | The p.I505T variant (also known as c.1514T>C), located in coding exon 10 of the CDH1 gene, results from a T to C substitution at nucleotide position 1514. The isoleucine at codon 505 is replaced by threonine, an amino acid with similar properties. This alteration has been reported with a carrier frequency of 0.00142 in 7051 unselected breast cancer patients and 0.00053 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat. Commun, 2018 10;9:4083). This amino acid position is not well 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. |
| Color Diagnostics, |
RCV001011874 | SCV001343995 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-11-11 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with threonine at codon 505 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193301 | SCV001362047 | uncertain significance | not specified | 2019-08-16 | criteria provided, single submitter | clinical testing | Variant summary: CDH1 c.1514T>C (p.Ile505Thr) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251472 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1514T>C in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Baylor Genetics | RCV004569618 | SCV005060075 | uncertain significance | Familial cancer of breast | 2024-02-23 | criteria provided, single submitter | clinical testing |