Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000034890 | SCV000623244 | pathogenic | Bloom syndrome | 2019-12-23 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Asn515Lysfs*2) in the BLM gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in the literature in individuals affected with Bloom syndrome (PMID: 7585968, 17407155). ClinVar contains an entry for this variant (Variation ID: 42064). Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). For these reasons, this variant has been classified as Pathogenic. |
| Integrated Genetics/Laboratory Corporation of America | RCV000034890 | SCV000918658 | pathogenic | Bloom syndrome | 2018-11-12 | criteria provided, single submitter | clinical testing | Variant summary: BLM c.1544dupA (p.Asn515LysfsX2) 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 (eg. c.1642C>T, p.Gln548X; c.2207_2212delinsTAGATTC, p.Tyr736fsX5). The variant was absent in 245606 control chromosomes (gnomAD). c.1544dupA has been reported in the literature in multiple individuals affected with Bloom Syndrome and indicated to be a Japanese founder mutation (Ellis_1995, German_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Ambry Genetics | RCV001012119 | SCV001172537 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-12-10 | criteria provided, single submitter | clinical testing | The c.1544dupA pathogenic mutation, located in coding exon 6 of the BLM gene, results from a duplication of A at nucleotide position 1544, causing a translational frameshift with a predicted alternate stop codon (p.N515Kfs*2). This mutation has been reported in the literature in individuals with Bloom syndrome (Ellis NA et al. Cell 1995 Nov;83(4):655-66; German J et al. Hum. Mutat. 2007 Aug;28(8):743-53). 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. |
| Cancer Genomics Group, |
RCV001030453 | SCV001193513 | likely pathogenic | Hereditary breast and ovarian cancer syndrome | 2019-05-01 | criteria provided, single submitter | research |