Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001321100 | SCV001511915 | uncertain significance | Bloom syndrome | 2022-10-07 | criteria provided, single submitter | clinical testing | This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 803 of the BLM protein (p.Trp803Arg). This variant is present in population databases (rs148394770, gnomAD 0.01%). 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: 1021353). 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"). Experimental studies have shown that this missense change affects BLM function (PMID: 23129629, 26788541). 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 | RCV002447359 | SCV002732699 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-10-26 | criteria provided, single submitter | clinical testing | The p.W803R variant (also known as c.2407T>C), located in coding exon 11 of the BLM gene, results from a T to C substitution at nucleotide position 2407. This variant impacts the first base pair of coding exon 11. The tryptophan at codon 803 is replaced by arginine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 11. Functional studies performed in yeast showed increased sensitivity to DNA damaging agents comparable to that of known BLM mutations (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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Baylor Genetics | RCV001321100 | SCV004210943 | likely pathogenic | Bloom syndrome | 2024-02-26 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004690077 | SCV005185071 | uncertain significance | not specified | 2024-05-22 | criteria provided, single submitter | clinical testing | Variant summary: BLM c.2407T>C (p.Trp803Arg) results in a non-conservative amino acid change located in the DEAD/DEAH box helicase domain (IPR011545) and Helicase superfamily 1/2, ATP-binding domain (IPR014001) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251416 control chromosomes. To our knowledge, no occurrence of c.2407T>C in individuals affected with Bloom Syndrome has been reported. Two studies from the same group reported a severe susceptibility to DNA-damaging agents in vitro in both chimeric S. cerevisiae strains and human Bloom syndrome (blm-Ash background) fibroblast cell lines (example, Mirzaei_2012, Shastri_2016). The following publications have been ascertained in the context of this evaluation (PMID: 23129629, 26788541). ClinVar contains an entry for this variant (Variation ID: 1021353). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |