ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.3475_3476del (p.Leu1159fs)

dbSNP: rs367543033
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000034910 SCV000486723 likely pathogenic Bloom syndrome 2016-07-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034910 SCV000916684 pathogenic Bloom syndrome 2023-08-10 criteria provided, single submitter clinical testing Variant summary: BLM c.3475_3476delTT (p.Leu1159IlefsX6) 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. Variants downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 4e-06 in 251414 control chromosomes (gnomAD). c.3475_3476delTT has been reported in the literature in an individual affected with Bloom Syndrome (example: German_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17407155, 26247052, 26358404). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000034910 SCV001406556 pathogenic Bloom syndrome 2023-11-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1159Ilefs*6) 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 present in population databases (rs367543033, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 42084). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002453293 SCV002613948 pathogenic Hereditary cancer-predisposing syndrome 2021-04-27 criteria provided, single submitter clinical testing The c.3475_3476delTT pathogenic mutation, located in coding exon 17 of the BLM gene, results from a deletion of two nucleotides at nucleotide positions 3475 to 3476, causing a translational frameshift with a predicted alternate stop codon (p.L1159Ifs*6). This alteration was detected in conjunction with the BLM c.2098C>T (p.Gln700X) alteration in a patient diagnosed with Bloom syndrome (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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