Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000115313 | SCV000149222 | uncertain significance | not provided | 2014-01-23 | 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.3892G>A at the cDNA level, p.Gly1298Arg (G1298R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Gly1298Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative substitution in which a neutral non-polar amino acid is replaced with a positive polar one, altering a position that is weakly conserved and tolerates the Gly>Arg change in many mammals. BLM Gly1298Arg is not located in a known functional domain (UniProt). In silico analyses predict this variant to have a benign effect on protein structure and function, and to have no effect on splicing. Based on currently available information, we consider this to be a variant of uncertain significance. Furthermore, cancer risks associated with this variant, and with single variants in the BLM gene in general, remain unclear. |
| Ambry Genetics | RCV000561783 | SCV000672952 | likely benign | Hereditary cancer-predisposing syndrome | 2017-08-24 | 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 |
RCV000628664 | SCV000749569 | uncertain significance | Bloom syndrome | 2023-12-15 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1298 of the BLM protein (p.Gly1298Arg). This variant is present in population databases (rs587779889, gnomAD 0.004%). 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: 127505). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. |
| Counsyl | RCV000628664 | SCV000796752 | uncertain significance | Bloom syndrome | 2017-12-28 | criteria provided, single submitter | clinical testing |