ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.274A>G (p.Asn92Asp) (rs200690226)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561733 SCV000672866 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000203080 SCV000257607 uncertain significance not specified 2015-06-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000462198 SCV000894957 uncertain significance Bloom syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000656777 SCV000149209 uncertain significance not provided 2014-02-19 criteria provided, single submitter clinical testing BLM has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted BLM c.274A>G at the cDNA level, p.Asn92Asp (N92D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Asn92Asp was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a semi-conservative substitution in which a neutral polar amino acid is replaced with a negative polar one, altering a position that is only moderately conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and 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 the BLM gene, remain unclear.
Invitae RCV000462198 SCV000543356 uncertain significance Bloom syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 92 of the BLM protein (p.Asn92Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs200690226, 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: 127493). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Mendelics RCV000462198 SCV000838945 uncertain significance Bloom syndrome 2018-07-02 criteria provided, single submitter clinical testing

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