ClinVar Miner

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

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000562058 SCV000672883 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000210906 SCV000264592 uncertain significance Bloom syndrome 2016-01-01 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656774 SCV000704456 uncertain significance not provided 2018-03-02 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
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.
GeneKor MSA RCV000562058 SCV000821898 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000115279 SCV000593630 uncertain significance not specified 2017-05-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000210906 SCV000394406 uncertain significance Bloom syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000115279 SCV000918648 uncertain significance not specified 2018-03-23 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 was observed with an allele frequency of 0.0011 in 269976 control chromosomes (gnomAD). 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. The variant, c.11T>C, has been reported in the literature in individuals affected with prostate cancer, non-Hodgkin lymphoma and breast cancer (Hunter_2016, Schuetz_2009, Thompson_2012). In the family reported 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. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites variant with conflicting classifications, predominantly as "uncertain significance," as well as a "benign." Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000210906 SCV000283111 benign Bloom syndrome 2018-01-04 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
Mendelics RCV000210906 SCV000838938 uncertain significance Bloom syndrome 2018-07-02 criteria provided, single submitter clinical testing

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