Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001021333 | SCV001182936 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-02-20 | criteria provided, single submitter | clinical testing | The p.A1292T variant (also known as c.3874G>A), located in coding exon 19 of the BLM gene, results from a G to A substitution at nucleotide position 3874. The alanine at codon 1292 is replaced by threonine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 19 and may have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. 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. |
Cancer Genomics Group, |
RCV001030461 | SCV001193521 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2019-05-01 | criteria provided, single submitter | research | |
Invitae | RCV001832350 | SCV002173137 | uncertain significance | Bloom syndrome | 2022-08-19 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1292 of the BLM protein (p.Ala1292Thr). This variant also falls at the last nucleotide of exon 20, which is part of the consensus splice site for this exon. This variant is present in population databases (rs757641454, gnomAD 0.03%). 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: 824326). 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 tolerated. 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. |
Natera, |
RCV001832350 | SCV002090619 | uncertain significance | Bloom syndrome | 2020-11-16 | no assertion criteria provided | clinical testing |