ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.1933C>T (p.Gln645Ter) (rs373525781)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000545144 SCV000623255 pathogenic Bloom syndrome 2019-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln645*) in the BLM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs373525781, ExAC 0.008%). This variant has been reported as a recurrent founder mutation in individuals with Bloom syndrome of European and North American origin (PMID: 17407155). This variant has also been reported in individuals with breast, ovarian or colorectal cancer (PMID: 23028338, 24448499, 27356891). ClinVar contains an entry for this variant (Variation ID: 454091). Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000576060 SCV000672860 pathogenic Hereditary cancer-predisposing syndrome 2017-02-23 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000545144 SCV000694474 pathogenic Bloom syndrome 2017-07-27 criteria provided, single submitter clinical testing Variant summary: The BLM c.1933C>T (p.Gln645X) variant results in a premature termination codon, predicted to cause a truncated or absent BLM 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 (e.g. c.2207_2212del6insTAGATTC, p.Tyr736fsX5; c.1968dupG, p.Lys657fsX5). One in silico tool predicts a damaging outcome for this variant. A functional study showed that in two homozygotes with this variant the signal from the mRNA detected in the Bloom Syndrome cell line was less than 20% of the signal detected in the mRNA from a normal cell line (German_2007). This variant was found in 5/124104 control chromosomes at a frequency of 0.0000403, which does not exceed the estimated maximal expected allele frequency of a pathogenic BLM variant (0.0035355). This variant was found in multiple patients with Bloom Syndrome in homozygotes and compound heterozygotes (German_2007). Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000545144 SCV000893389 pathogenic Bloom syndrome 2018-10-31 criteria provided, single submitter clinical testing

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