ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.1928G>A (p.Arg643His) (rs12720097)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000116502 SCV000149195 likely benign not specified 2017-09-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CSER _CC_NCGL, University of Washington RCV000211548 SCV000212202 uncertain significance Bloom syndrome 2015-03-11 criteria provided, single submitter research
Invitae RCV000857778 SCV000283117 benign not provided 2019-03-05 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000116502 SCV000301735 likely benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000116502 SCV000331364 likely benign not specified 2016-08-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000211548 SCV000394415 uncertain significance Bloom syndrome 2016-06-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565415 SCV000672884 likely benign Hereditary cancer-predisposing syndrome 2018-12-21 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000116502 SCV000916681 likely benign not specified 2018-07-03 criteria provided, single submitter clinical testing Variant summary: BLM c.1928G>A (p.Arg643His) results in a non-conservative amino acid change located in the Bloom syndrome protein, BDHCT-box associated domain (IPR032439) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 276144 control chromosomes, predominantly at a frequency of 0.0045 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3-fold of the estimated maximal expected allele frequency for a pathogenic variant in BLM causing Bloom Syndrome phenotype (0.0035), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.1928G>A, has been reported in the literature in individuals affected with breast cancer (Thompson_2012) and as a somatic events in glioblastoma and Mullerian adenosarcoma (Burzynski_2015, Howitt_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Cancer and/or Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS x2, likely benign x3, benign x1). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000857778 SCV001149588 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
ITMI RCV000116502 SCV000084399 not provided not specified 2013-09-19 no assertion provided reference population
Genetic Services Laboratory, University of Chicago RCV000116502 SCV000150446 likely benign not specified no assertion criteria provided clinical testing Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

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