Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV000989396 | SCV001139711 | likely pathogenic | Bloom syndrome | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000989396 | SCV001532499 | uncertain significance | Bloom syndrome | 2022-03-20 | criteria provided, single submitter | clinical testing | This variant is present in population databases (no rsID available, gnomAD 0.01%). 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. This variant disrupts the p.Cys1055 amino acid residue in BLM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7585968, 9840919, 10069810, 11399766, 17407155, 28877996). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 803137). This variant has not been reported in the literature in individuals affected with BLM-related conditions. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1055 of the BLM protein (p.Cys1055Tyr). |
| Ambry Genetics | RCV002320201 | SCV002608500 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-05-12 | criteria provided, single submitter | clinical testing | The p.C1055Y variant (also known as c.3164G>A), located in coding exon 15 of the BLM gene, results from a G to A substitution at nucleotide position 3164. The cysteine at codon 1055 is replaced by tyrosine, an amino acid with highly dissimilar properties. Based on internal structural analysis, p.C1055Y is strongly disruptive to the structure of the zinc-binding domain of BLM, and abrogates an interaction with the zinc ion at position with known pathogenic variants (Guo RB et al. Nucleic Acids Res., 2005 Jun;33:3109-24; Swan MK et al. Acta Crystallogr. D Biol. Crystallogr., 2014 May;70:1465-75; Newman JA et al. Nucleic Acids Res., 2015 May;43:5221-35). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). A different alteration at this position, p.C1055G, has been found in one patient with Bloom syndrome who also has an Ashkenazi Jewish founder mutation (German J et al. Hum. Mutat., 2007 Aug;28:743-53; Shastri VM et al. Mol Genet Genomic Med, 2016 Jan;4:106-19). A second alteration at this position, p.C1055S, has been reported in the literature in both a homozygous and compound heterozygous state in individuals with Bloom syndrome (Ellis NA et al. Cell, 1995 Nov;83:655-66; German J et al. Hum. Mutat., 2007 Aug;28:743-53) and functional studies have demonstrated that p.C1055S causes reduced BLM protein expression and lacks detectable helicase and DNA-dependent ATPase activities, which are essential for wild-type interaction of BLM with tp53 in the DNA damage response pathway (Wang XW et al. J. Biol. Chem., 2001 Aug;276:32948-55; Neff NF et al. Mol. Biol. Cell, 1999 Mar;10:665-76). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003478602 | SCV004222474 | uncertain significance | not provided | 2023-01-20 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population, 0.000004 (1/248860 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported to cause structural disruption and result in loss of Zinc binding using computational tools (PMID: 32704157 (2020)). Other variants at this amino acid position have also been reported to be damaging to protein function (PMID: 15930159 (2005)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. |
| Natera, |
RCV000989396 | SCV002090522 | uncertain significance | Bloom syndrome | 2020-06-19 | no assertion criteria provided | clinical testing |