ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.191A>T (p.Asp64Val) (rs140382474)

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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 RCV000574815 SCV000672903 likely benign Hereditary cancer-predisposing syndrome 2017-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656775 SCV000228762 uncertain significance not provided 2015-04-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000460513 SCV000611375 uncertain significance Bloom syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000656775 SCV000149194 uncertain significance not provided 2014-03-10 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.191A>T at the cDNA level, p.Asp64Val (D64V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Asp64Val was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a non-conservative substitution of a negative polar amino acid for a neutral non-polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. Multiple in silico algorithms predict that this variant may be damaging to 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 with single variants the BLM gene in general, remain unclear.
GeneKor MSA RCV000574815 SCV000821900 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000460513 SCV000543353 uncertain significance Bloom syndrome 2019-01-11 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 64 of the BLM protein (p.Asp64Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs140382474, ExAC 0.06%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals with BLM-related disease. ClinVar contains an entry for this variant (Variation ID: 127479). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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