ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs587779893
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115320 SCV000149229 uncertain significance not provided 2023-07-11 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp RCV000464245 SCV000543388 uncertain significance Bloom syndrome 2025-01-29 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 181 of the BLM protein (p.Ser181Ile). This variant is present in population databases (rs587779893, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 127512). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Ambry Genetics RCV000567877 SCV000672910 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-28 criteria provided, single submitter clinical testing The p.S181I variant (also known as c.542G>T), located in coding exon 2 of the BLM gene, results from a G to T substitution at nucleotide position 542. The serine at codon 181 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000115320 SCV002010747 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000567877 SCV002533129 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-08 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002281933 SCV002570726 uncertain significance not specified 2022-07-17 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000464245 SCV003928061 uncertain significance Bloom syndrome 2023-03-27 criteria provided, single submitter clinical testing The BLM c.542G>T (p.Ser181Ile) missense change has a maximum subpopulation frequency of 0.0079% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Bloom syndrome.  In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. 
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115320 SCV004222504 uncertain significance not provided 2023-09-21 criteria provided, single submitter clinical testing This variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000079 (10/126474 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc. RCV000464245 SCV001456982 uncertain significance Bloom syndrome 2018-06-02 no assertion criteria provided clinical testing

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