ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.3427G>A (p.Glu1143Lys) (rs140387675)

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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 RCV000566047 SCV000672921 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000115307 SCV000149216 uncertain significance not provided 2013-10-23 criteria provided, single submitter clinical testing This variant, in exon 18 of the BLM gene, is denoted c.3427G>A at the cDNA level and p.Glu1143Lys (E1143K) at the protein level. This amino acid substitution results in the non-conservative replacement of a negatively-charged Glutamic Acid residue (GAA) with a positively-charged Lysine residue (AAA) at a position that is well-conserved throughout evolution. Glu1143Lys is located within the RecQ C-terminal domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Glu1143Lys has not been published in the literature as a mutation nor has it been reported as a benign polymorphism, to our knowledge. The NHLBI ESP Exome Variant Server reports that Glu1143Lys was not observed with significant allele frequency in approximately 6500 individual of European and African American backgrounds, suggesting it is not a common benign variant in these populations. A functional evaluation showed that this variant was equivalent in expression to the wild-type allele (Mizraei 2012). Therefore, based on the currently available information, it is unclear whether Glu1143Lys is a pathogenic mutation or a rare benign variant.The variant is found in HEREDICANCER panel(s).
GeneKor MSA RCV000566047 SCV000821904 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000475273 SCV000543395 uncertain significance Bloom syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1143 of the BLM protein (p.Glu1143Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs140387675, ExAC 0.02%). This variant has not been reported in the literature in individuals with BLM-related disease. ClinVar contains an entry for this variant (Variation ID: 127499). Experimental studies have shown that this variant does not disrupt BLM protein function in a yeast model (PMID: 23129629). However, the clinical significance of this result is uncertain. 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.
Mendelics RCV000475273 SCV000838984 uncertain significance Bloom syndrome 2018-07-02 criteria provided, single submitter clinical testing

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