ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.368A>G (p.Gln123Arg) (rs371223446)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000473466 SCV000896478 uncertain significance Bloom syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000115311 SCV000149220 uncertain significance not provided 2014-03-03 criteria provided, single submitter clinical testing Single mutation 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.368A>G at the cDNA level, p.Gln123Arg (Q123R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Gln123Arg was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution and may affect protein integrity. BLM Gln123Arg occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or 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 the BLM gene in general, remain unclear.
Invitae RCV000473466 SCV000543326 uncertain significance Bloom syndrome 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 123 of the BLM protein (p.Gln123Arg). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs371223446, ExAC 0.009%). This variant has been reported to segregate with prostate cancer in a single family, however 3 additional variants in 3 different genes also segregated with disease in this family (PMID: 25111073). ClinVar contains an entry for this variant (Variation ID: 127503). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but 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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