Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000131558 | SCV000186561 | likely benign | Hereditary cancer-predisposing syndrome | 2024-11-14 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Labcorp Genetics |
RCV000205207 | SCV000261601 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2024-02-01 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 794 of the CDH1 protein (p.Val794Ile). This variant is present in population databases (rs587782466, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 142437). 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. |
Gene |
RCV000484196 | SCV000570243 | uncertain significance | not provided | 2019-01-04 | criteria provided, single submitter | clinical testing | This variant is denoted CDH1 c.2380G>A at the cDNA level, p.Val794Ile (V794I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 Val794Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the hakai binding region of the cytoplasmic domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDH1 Val794Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Color Diagnostics, |
RCV000131558 | SCV000684429 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-16 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with isoleucine at codon 794 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 32885271, 32885271, 33471991). This variant has been identified in 3/282818 chromosomes 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. |
Counsyl | RCV000205207 | SCV000784938 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2017-02-08 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000131558 | SCV002529129 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-10-30 | criteria provided, single submitter | curation | |
Myriad Genetics, |
RCV000205207 | SCV004020019 | uncertain significance | Hereditary diffuse gastric adenocarcinoma | 2023-03-06 | criteria provided, single submitter | clinical testing | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. |
Institute for Biomarker Research, |
RCV000131558 | SCV005205776 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-07-09 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV005016451 | SCV005644359 | uncertain significance | Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian cancer | 2024-02-28 | criteria provided, single submitter | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV001354689 | SCV001549366 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The CDH1 p.Val794Ile variant was not identified in the literature nor was it identified in Cosmic, MutDB, or Zhejiang University Database. The variant was identified in dbSNP (ID: rs587782466) as “With Uncertain significance allele” and ClinVar (4x as uncertain significance). The variant was also identified in control databases in 2 of 277170 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24030 chromosomes (freq: 0.00004), Latino in 1 of 34420 chromosomes (freq: 0.00003); it was not observed in the “Other”, European Non-Finnish, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant is located in the cytoplasmic domain and the Hakai-binding region, where missense mutations have been suggested to cause decreased stability at the plasma membrane and may result in higher endocytosis (Figueiredo 2013). The p.Val794 residue is not conserved in mammals and Valine and Isoleucine have similar biochemical properties. In addition, 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |