ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2506_2507del (p.Arg836fs) (rs367543024)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000034897 SCV000486883 pathogenic Bloom syndrome 2016-08-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000574956 SCV000672963 pathogenic Hereditary cancer-predisposing syndrome 2017-06-22 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000034897 SCV000749524 pathogenic Bloom syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg836Glyfs*18) in the BLM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs367543024, ExAC 0.06%). This variant has been reported in individuals affected with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 42071). 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 RCV000034897 SCV001338365 likely pathogenic Bloom syndrome 2020-02-17 criteria provided, single submitter clinical testing Variant summary: BLM c.2506_2507delAG (p.Arg836GlyfsX18) 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.2695C>T, p.Arg899X; c.3028delG, p.Asp1010MetfsX24). The variant allele was found at a frequency of 7.6e-05 in 251380 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BLM causing Bloom Syndrome (7.6e-05 vs 0.0035), allowing no conclusion about variant significance c.2506_2507delAG has been reported in the literature in individuals affected with Bloom Syndrome (German_2007). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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