ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2357G>A (p.Arg786Lys)

gnomAD frequency: 0.00001  dbSNP: rs369065966
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000687762 SCV000815348 uncertain significance Bloom syndrome 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 786 of the BLM protein (p.Arg786Lys). This variant is present in population databases (rs369065966, gnomAD 0.002%). 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: 567621). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BLM protein function with a negative predictive value of 80%. 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 RCV001015279 SCV001176095 uncertain significance Hereditary cancer-predisposing syndrome 2024-07-27 criteria provided, single submitter clinical testing The p.R786K variant (also known as c.2357G>A), located in coding exon 10 of the BLM gene, results from a G to A substitution at nucleotide position 2357. The arginine at codon 786 is replaced by lysine, an amino acid with highly similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This alteration was also identified in a cohort of early onset colorectal cancer patients (Belhadj S et al. Hum Mutat, 2020 09;41:1563-1576). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000687762 SCV001775507 uncertain significance Bloom syndrome 2021-07-29 criteria provided, single submitter clinical testing The BLM c.2357G>A (p.Arg786Lys) missense change has a maximum subpopulation frequency of 0.0018% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/15-91312412-G-A). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant has been identified in 1 of 1358 control individuals collected as part of non-cancer studies (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with Bloom syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV004997145 SCV005624249 uncertain significance not provided 2023-12-15 criteria provided, single submitter clinical testing The BLM c.2357G>A (p.Arg786Lys) variant has been reported in the published literature in at least one reportedly healthy individual (PMID: 29641532 (2018)), and in an individual with familial/early-onset colorectal cancer (PMID: 32449991 (2020)). The frequency of this variant in the general population, 0.000008 (2/251474 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. RCV000687762 SCV002088059 uncertain significance Bloom syndrome 2020-12-15 no assertion criteria provided clinical testing

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