Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000586500 | SCV000694475 | pathogenic | Bloom syndrome | 2019-12-01 | criteria provided, single submitter | clinical testing | Variant summary: BLM c.1968dupG (p.Lys657GlufsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251206 control chromosomes. c.1968dupG has been reported in the literature in at-least one homozygous individual born to consanguineous parents, affected with Bloom Syndrome and included in the Bloom syndrome registry (German_2007). It has subsequently been cited as a pathogenic variant in reports of carrier screening for BLM syndrome (Perreault-Micale_2015) and other literature (de Voer_2015, Salah_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The variant has been observed at-least twice among individuals undergoing carrier screening at our laboratory. No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was re-classified as pathogenic. |
| Ambry Genetics | RCV001013870 | SCV001174506 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-02-27 | criteria provided, single submitter | clinical testing | The c.1968dupG pathogenic mutation, located in coding exon 7 of the BLM gene, results from a duplication of G at nucleotide position 1968, causing a translational frameshift with a predicted alternate stop codon (p.K657Efs*5). This alteration has been reported in a cohort of 134 persons with Bloom syndrome (BS) from the Bloom's Syndrome Registry (German J et al. Hum. Mutat., 2007 Aug;28:743-53). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV000586500 | SCV001209121 | pathogenic | Bloom syndrome | 2023-12-27 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Lys657Glufs*5) in the BLM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). This variant is present in population databases (rs772785079, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 495425). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. |
| Counsyl | RCV000586500 | SCV001132141 | likely pathogenic | Bloom syndrome | 2015-03-16 | no assertion criteria provided | clinical testing | |
| Natera, |
RCV000586500 | SCV002088019 | pathogenic | Bloom syndrome | 2017-03-16 | no assertion criteria provided | clinical testing |