ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.3397A>G (p.Lys1133Glu) (rs145027663)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567551 SCV000672907 likely benign Hereditary cancer-predisposing syndrome 2017-07-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign)
GeneDx RCV000115306 SCV000149215 uncertain significance not provided 2014-02-25 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.3397A>G at the cDNA level, p.Lys1133Glu (K1133E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Lys1133Glu was observed with an allele frequency of 0.1% (5/4396) in African Americans in the NHLBI Exome Sequencing Project, not frequent enough to be considered a polymorphism. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution and is likely to affect protein integrity. BLM Lys1133Glu occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. At 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 the BLM gene in general, remain unclear.
Invitae RCV000542140 SCV000623312 uncertain significance Bloom syndrome 2018-05-13 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 1133 of the BLM protein (p.Lys1133Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs145027663, ExAC 0.05%). This variant has not been reported in the literature in individuals with BLM-related disease. ClinVar contains an entry for this variant (Variation ID: 127498). An experimental study in yeast has shown that this variant behaves like wild-type in an assay measuring sensitivity to DNA damaging agents (PMID: 23129629). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.