Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000218940 | SCV000277392 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-03-08 | criteria provided, single submitter | clinical testing | The p.R779W variant (also known as c.2335C>T), located in coding exon 15 of the CDH1 gene, results from a C to T substitution at nucleotide position 2335. The arginine at codon 779 is replaced by tryptophan, an amino acid with dissimilar properties. 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. |
| Labcorp Genetics |
RCV000457635 | SCV000545428 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2023-08-28 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 779 of the CDH1 protein (p.Arg779Trp). This missense change has been observed in individual(s) with colorectal cancer and/or juvenile polyps (PMID: 27146957, 33193653). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 233087). |
| Gene |
RCV000484296 | SCV000569596 | uncertain significance | not provided | 2024-03-15 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in individuals with personal or family history of colorectal cancer or with juvenile polyps (PMID: 27146957, 33193653); Observed in cancer free controls and not observed in any biliary tract cancer cases in a case control study (PMID: 36243179); This variant is associated with the following publications: (PMID: 27146957, 17545690, 33193653, 36243179, 15235021, 22850631) |
| Color Diagnostics, |
RCV000218940 | SCV000689512 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-07-16 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with tryptophan at codon 779 of the CDH1 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in an individual affected with juvenile polyposis (PMID: 27146957) however the variant was also observed in the proband's unaffected father (PMID: 27477802). 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, |
RCV000780099 | SCV000917141 | uncertain significance | not specified | 2018-12-07 | criteria provided, single submitter | clinical testing | Variant summary: CDH1 c.2335C>T (p.Arg779Trp) results in a non-conservative amino acid change located in the Cadherin, cytoplasmic domain 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 246242 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2335C>T has been reported in the literature in one individual affected with juvenile polyps (Jelsig_2016a). Samples from the parents revealed that the variant was inherited from the father, who is healthy (Jelsig_2016b), indicating lack of co-segregation of this variant and juvenile polyps condition. These reports do not provide conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Baylor Genetics | RCV004567631 | SCV005060054 | uncertain significance | Familial cancer of breast | 2024-03-22 | criteria provided, single submitter | clinical testing |