ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.542G>T (p.Ser181Ile) (rs587779893)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567877 SCV000672910 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000115320 SCV000149229 uncertain significance not provided 2014-03-03 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.542G>T at the cDNA level, p.Ser181Ile (S181I) at the protein level, and results in the change of a Serine to an Isoleucine (AGC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Ser181Ile 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. Since Serine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution and is likely to affect protein integrity. BLM Ser181Ile occurs at a position that is moderately conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have 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 RCV000464245 SCV000543388 uncertain significance Bloom syndrome 2017-12-20 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 181 of the BLM protein (p.Ser181Ile). The serine residue is moderately conserved and there is a large physicochemical difference between serine and isoleucine. This variant is present in population databases (rs587779893, ExAC 0.006%). This variant has not been reported in the literature in individuals with BLM-related disease. ClinVar contains an entry for this variant (Variation ID: 127512). 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: "Tolerated"; PolyPhen-2: "Probably 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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