Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000549947 | SCV000623221 | uncertain significance | Bloom syndrome | 2024-01-28 | 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 363 of the BLM protein (p.Ala363Thr). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (rs200364297, gnomAD 0.1%). 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: 454062). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). 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 | RCV001017173 | SCV001178210 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-19 | criteria provided, single submitter | clinical testing | The c.1087G>A variant (also known as p.A363T), located in coding exon 4 of the BLM gene, results from a G to A substitution at nucleotide position 1087. The amino acid change results in alanine to threonine at codon 363, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 4, which makes it likely to 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 will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration 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. |
| St. |
RCV000549947 | SCV002526091 | uncertain significance | Bloom syndrome | 2022-01-06 | criteria provided, single submitter | clinical testing | The BLM c.1087G>A (p.Ala363Thr) missense change has a maximum subpopulation frequency of 0.088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/15-91298168-G-A). This variant is located adjacent to the donor splice site of intron 5. This variant is predicted to result in loss of the native splice donor site (PP3) and skipping of exon 5 has been confirmed by RNA studies (PS3_supporting; internal data). To our knowledge, this variant has not been reported in individuals with Bloom syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS3_supporting, PP3. |
| Natera, |
RCV000549947 | SCV002090006 | uncertain significance | Bloom syndrome | 2018-10-16 | no assertion criteria provided | clinical testing |