ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.3044C>T (p.Thr1015Ile) (rs202196488)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570913 SCV000672908 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000115302 SCV000149211 uncertain significance not provided 2014-01-27 criteria provided, single submitter clinical testing Single pathogenic variants in BLM have only recently been described in association with cancer predisposition and the risks are not well understood. This variant is denoted BLM c.3044C>T at the cDNA level, p.Thr1015Ile (T1015I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Thr1015Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative substitution of a neutral polar amino acid for a neutral non-polar one, altering a position that is well conserved throughout evolution and is located in the Helicase C-terminal domain per UNIPROT and Interpro. Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and with single variants in BLM in general, remain unclear.
Invitae RCV000473191 SCV000543349 uncertain significance Bloom syndrome 2018-12-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1015 of the BLM protein (p.Thr1015Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs202196488, ExAC 0.02%). This variant has not been reported in the literature in individuals with a BLM-related disease. ClinVar contains an entry for this variant (Variation ID: 127494). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on BLM function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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