ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2250_2251insAAAT (p.Leu751fs) (rs786204471)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169119 SCV000220322 likely pathogenic Bloom syndrome 2014-05-15 criteria provided, single submitter literature only
Invitae RCV000169119 SCV000283120 pathogenic Bloom syndrome 2020-09-21 criteria provided, single submitter clinical testing This sequence change inserts 4 nucleotides in exon 10 of the BLM mRNA (c.2250_2251insAAAT), causing a frameshift at codon 751. This creates a premature translational stop signal (p.Leu751Lysfs*25) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in BLM are known to be pathogenic. This particular variant has been reported as heterozygous with pathogenic mutations in the BLM gene in two unrelated individuals in the Bloom's Syndrome Registry (PMID: 17407155). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001014933 SCV001175706 pathogenic Hereditary cancer-predisposing syndrome 2019-07-17 criteria provided, single submitter clinical testing The c.2250_2251insAAAT variant, located in coding exon 9 of the BLM gene, results from an insertion of 4 nucleotides at position 2250, causing a translational frameshift with a predicted alternate stop codon (p.L751Kfs*25). This alteration has been detected in the compound heterozygous state in two individuals affected with Bloom syndrome (German J et al. Hum. Mutat. 2007 Aug;28:743-53). This alteration has also been detected in a patient affected with colorectal cancer (AlDubayan SH et al. Am. J. Hum. Genet. 2018 03;102:401-414). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169119 SCV001482241 pathogenic Bloom syndrome 2021-02-13 criteria provided, single submitter clinical testing Variant summary: BLM c.2250_2251insAAAT (p.Leu751LysfsX25) 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 8e-06 in 250286 control chromosomes. c.2250_2251insAAAT has been reported in the literature in at-least two individuals with Bloom syndrome (German_2007) and in heterozygote carrier individuals tested in studies evaluating inherited DNA-repair defects in patients with colorectal cancer (AlDubayan_2018) and germline BLM mutations in metastatic prostate cancer (Ledet_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

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