ClinVar Miner

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

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000857778 SCV000149195 likely benign not provided 2020-12-01 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24728327)
CSER _CC_NCGL, University of Washington RCV000211548 SCV000212202 uncertain significance Bloom syndrome 2015-03-11 criteria provided, single submitter research
Invitae RCV000211548 SCV000283117 benign Bloom syndrome 2020-12-03 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 likely benign Bloom syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Ambry Genetics RCV000565415 SCV000672884 likely benign Hereditary cancer-predisposing syndrome 2018-12-21 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Nilou-Genome Lab RCV000211548 SCV001737334 likely benign Bloom syndrome 2021-06-10 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000857778 SCV001808140 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000116502 SCV001930149 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000116502 SCV001951297 benign not specified no assertion criteria provided clinical testing

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