ClinVar Miner

Submissions for variant NM_000057.3(BLM):c.3892G>A (p.Gly1298Arg) (rs587779889)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561783 SCV000672952 likely benign Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Counsyl RCV000628664 SCV000796752 uncertain significance Bloom syndrome 2017-12-28 criteria provided, single submitter clinical testing
GeneDx RCV000115313 SCV000149222 uncertain significance not provided 2014-01-23 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.3892G>A at the cDNA level, p.Gly1298Arg (G1298R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Gly1298Arg 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 in which a neutral non-polar amino acid is replaced with a positive polar one, altering a position that is weakly conserved and tolerates the Gly>Arg change in many mammals. BLM Gly1298Arg is not located in a known functional domain (UniProt). In silico analyses predict this variant to have a benign effect on protein structure and function, and to have no effect on splicing. Based on currently available information, we consider this to be a variant of uncertain significance. Furthermore, cancer risks associated with this variant, and with single variants in the BLM gene in general, remain unclear.
Invitae RCV000628664 SCV000749569 uncertain significance Bloom syndrome 2018-05-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1298 of the BLM protein (p.Gly1298Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs587779889, ExAC 0.001%). This variant has not been reported in the literature in individuals with BLM-related disease. ClinVar contains an entry for this variant (Variation ID: 127505). 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 and their clinical significance 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.

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