ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.991_995del (p.Lys331fs) (rs786204524)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169224 SCV000220489 likely pathogenic Bloom syndrome 2014-07-08 criteria provided, single submitter literature only
Invitae RCV000169224 SCV000833351 pathogenic Bloom syndrome 2018-06-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys331Glyfs*4) in the BLM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs748240187, ExAC 0.002%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in individuals affected with Bloom syndrome (PMID: 17407155). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 188870). Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169224 SCV000916686 likely pathogenic Bloom syndrome 2018-08-17 criteria provided, single submitter clinical testing Variant summary: BLM c.991_995delAAAGA (p.Lys331GlyfsX4) 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 (e.g. p.Trp428X, p.Asn515fsX16, p.Gln548X). The variant allele was found at a frequency of 7.2e-06 in 276670 control chromosomes (gnomAD). c.991_995delAAAGA 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics RCV001019885 SCV001181297 pathogenic Hereditary cancer-predisposing syndrome 2019-04-09 criteria provided, single submitter clinical testing The c.991_995delAAAGA pathogenic mutation, located in coding exon 4 of the BLM gene, results from a deletion of 5 nucleotides at nucleotide positions 991 to 995, causing a translational frameshift with a predicted alternate stop codon (p.K331Gfs*4). Two individuals with Bloom syndrome were reported to be heterozygous for this alteration and another BLM gene mutation (German J et al. Hum. Mutat. 2007 Aug;28:743-53). 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.

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