Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001020077 | SCV001181508 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-10 | criteria provided, single submitter | clinical testing | The c.3358G>C variant (also known as p.G1120R), located in coding exon 16 of the BLM gene, results from a G to C substitution at nucleotide position 3358. The amino acid change results in glycine to arginine at codon 1120, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. Functional studies found p.G1120R to be partially deficient with respect to chromosome abnormalities and response and sensitivity to DNA damaging agents (Mirzaei H et al. Proc. Natl. Acad. Sci. U.S.A., 2012 Nov;109:19357-62; Shastri VM et al. Mol Genet Genomic Med, 2016 Jan;4:106-19). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001860972 | SCV002128553 | uncertain significance | Bloom syndrome | 2021-08-12 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with arginine at codon 1120 of the BLM protein (p.Gly1120Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 17, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). 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: 823657). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BLM function (PMID: 23129629, 26788541). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |