ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.11T>C (p.Val4Ala) (rs144706057)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656774 SCV000149188 uncertain significance not provided 2018-07-23 criteria provided, single submitter clinical testing The V4A variant in the BLM gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V4A variant is observed in 304/269976 (0.11%) alleles in large population cohorts (Lek et al., 2016). The V4A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret V4A as a variant of uncertain significance.
CSER _CC_NCGL, University of Washington RCV000210906 SCV000264592 uncertain significance Bloom syndrome 2016-01-01 criteria provided, single submitter research
Invitae RCV000210906 SCV000283111 benign Bloom syndrome 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000210906 SCV000394406 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.
Genetic Services Laboratory,University of Chicago RCV000115279 SCV000593630 uncertain significance not specified 2017-05-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000210906 SCV000611374 uncertain significance Bloom syndrome 2017-05-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562058 SCV000672883 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-16 criteria provided, single submitter clinical testing Insufficient evidence
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656774 SCV000704456 uncertain significance not provided 2018-03-02 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000210906 SCV000809075 uncertain significance Bloom syndrome 2016-08-02 criteria provided, single submitter clinical testing
GeneKor MSA RCV000562058 SCV000821898 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000210906 SCV000838938 uncertain significance Bloom syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000115279 SCV000918648 uncertain significance not specified 2019-05-02 criteria provided, single submitter clinical testing Variant summary: BLM c.11T>C (p.Val4Ala) results in a non-conservative amino acid change located in the Bloom syndrome protein, N-terminal domain 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 0.0011 in 245310 control chromosomes, predominantly at a frequency of 0.0022 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BLM causing Bloom Syndrome (0.0011 vs 0.0035), allowing no conclusion about variant significance. c.11T>C has been reported in the literature in individuals affected with Prostate cancer, NHL, and in HBOC families (Hunter_2016, Schuetz_2009, Thompson_2012, Bonache_2018). Specifically, in the family with prostate cancer, the variant did not segregate with disease (Hunter_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Ten submitters report a classification as VUS and one a benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656774 SCV001334805 uncertain significance not provided 2020-02-01 criteria provided, single submitter clinical testing

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