Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000115282 | SCV000149191 | uncertain significance | not provided | 2014-02-21 | criteria provided, single submitter | clinical testing | Single pathogenic variants in BLM have only recently been described in association with cancer predisposition and the risks are not well understood. This variant is denoted BLM c.1348A>G at the cDNA level, p.Met450Val (M450V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Met450Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This is a conservative amino acid substitution which is unlikely to impact secondary protein structure since Methionine and Valine share similar properties. BLM Met450Val occurs at a position that is highly variable across species and is located within the region necessary for interaction with scaffolding protein involved in DNA repair (SPIDR). In silico analyses predict this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BLM Met450Val is pathogenic or benign. We consider it to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and with single variants the BLM gene in general, remain unclear. |
| Labcorp Genetics |
RCV001222033 | SCV001394112 | uncertain significance | Bloom syndrome | 2024-10-16 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 450 of the BLM protein (p.Met450Val). This variant is present in population databases (rs200385935, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 127476). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BLM protein function with a negative predictive value of 80%. 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 | RCV002381418 | SCV002693331 | likely benign | Hereditary cancer-predisposing syndrome | 2022-02-03 | 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. |
| Natera, |
RCV001222033 | SCV001460779 | uncertain significance | Bloom syndrome | 2020-09-16 | no assertion criteria provided | clinical testing |