ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2720C>T (p.Thr907Met) (rs367953471)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566952 SCV000672927 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000461478 SCV000796754 uncertain significance Bloom syndrome 2017-12-28 criteria provided, single submitter clinical testing
GeneDx RCV000115299 SCV000149208 uncertain significance not provided 2014-01-14 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.2720C>T at the cDNA level, p.Thr907Met (T907M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Thr907Met was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a non-conservative substitution in which a neutral polar amino acid is replaced with a neutral non-polar one, altering a position that is well conserved throughout evolution and is located in the Helicase C-terminal domain (UniProt). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on the currently available information, we consider BLM Thr907Met to be a variant of uncertain significance. Furthermore, cancer risks associated with this variant, and with single variants the BLM gene in general, remain unclear.
Invitae RCV000461478 SCV000543333 uncertain significance Bloom syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 907 of the BLM protein (p.Thr907Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs367953471, ExAC 0.04%) but has not been reported in the literature in individuals with a BLM-related disease. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000461478 SCV000838979 uncertain significance Bloom syndrome 2018-07-02 criteria provided, single submitter clinical testing

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