Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000336886 | SCV000394417 | pathogenic | Bloom syndrome | 2017-04-27 | criteria provided, single submitter | clinical testing | The BLM c.2206dupT (p.Tyr736LeufsTer5), also known as c.2207_2212delinsTAGATTC or BLMAsh, results in a frameshift and is predicted to result in premature termination of the protein. The p.Tyr736LeufsTer5 variant is a known common pathogenic founder variant in the Ashkenazi Jewish population asociated with Bloom syndrome (Sanz et al. 2013). The p.Tyr736LeufsTer5 variant has been reported in at least three studies in which it is found in a total of 44 individuals with Bloom syndrome including in 34 in a homozygous state and in ten in a compound heterozygous state (Ellis et al. 1995; Ellis et al. 1998; German et al. 2007). The p.Tyr736LeufsTer5 variant has been found in a heterozygous state in 19 out of 2998 healthy controls and is reported at a frequency of 0.00037 in the European American population of the Exome Sequencing Project (Oddoux et al. 1999; Gruber et al. 2002). Functional studies in the GM08505 cell line showed the variant resulted in significantly higher sister-chromatid exchanges, a delayed DNA damage response and inefficient DNA repair (Shastri and Schmidt 2015). Based on the collective evidence and the potential impact of frameshift variants, the p.Tyr736LeufsTer5 variant is classified as pathogenic for Bloom syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Invitae | RCV000336886 | SCV001592163 | pathogenic | Bloom syndrome | 2022-09-30 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Tyr736Leufs*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 not present in population databases (gnomAD no frequency). This particular variant is a well documented pathogenic founder variant in Bloom syndrome in individuals of Ashkenazi Jewish ancestry (PMID: 7585968, 9758720). It is present at a carrier rate of 1/107 unaffected individuals of Ashkenazi Jewish ancestry (PMID: 9758720, 9837821). This variant is also known as blm-Ash; 6-bp deletion and 7-bp insertion at nt 2281. ClinVar contains an entry for this variant (Variation ID: 5454). For these reasons, this variant has been classified as Pathogenic. |