ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2371C>T (p.Arg791Cys) (rs55880859)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568596 SCV000672919 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000628631 SCV000749535 uncertain significance Bloom syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 791 of the BLM protein (p.Arg791Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs55880859, ExAC 0.2%). This variant has not been reported in the literature in individuals with BLM-related disease. ClinVar contains an entry for this variant (Variation ID: 133698). Experimental studies have shown that this missense change may result in a partial loss of function of BLM protein (PMID: 23129629, 26788541, 24816114). 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.
Counsyl RCV000628631 SCV000790160 uncertain significance Bloom syndrome 2017-03-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000628631 SCV000896483 uncertain significance Bloom syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120226 SCV000918647 uncertain significance not specified 2018-02-23 criteria provided, single submitter clinical testing Variant summary: BLM c.2371C>T (p.Arg791Cys) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain and DEAD/DEAH box helicase domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 277226 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BLM causing Bloom Syndrome (0.00012 vs 0.0035), allowing no conclusion about variant significance. The c.2371C>T variant has been reported in the literature in a cancer cell line from a Bloom Syndrome patient. This report does not provide strong evidence about an association of the variant with Bloom Syndrome. Several publications report experimental evidence evaluating an impact on protein function. In one study (Shastri_2015), the variant showed no significant sensitivity to hydroxyurea. However, it showed delayed accumulation and elimination of phosphorylated H2AX upon DNA damage. Moreover, the variant showed a significantly increased level of sister chromatid exchanges compared WT controls. Another study (Mirzaei_2012) described the variant as a partial loss of function via yeast growth assays, and suggested this was due to the variants proximity to an invariant residue (D795), thus causing only a partial loss of ATP hydrolysis activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
ITMI RCV000120226 SCV000084372 not provided not specified 2013-09-19 no assertion provided reference population

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