ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.3164G>C (p.Cys1055Ser) (rs367543029)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569697 SCV000672962 pathogenic Hereditary cancer-predisposing syndrome 2017-04-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Other data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000034904 SCV000749572 likely pathogenic Bloom syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 1055 of the BLM protein (p.Cys1055Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is present in population databases (rs367543029, ExAC 0.003%). This variant has been reported as homozygous and compound heterozygous in individuals affected with Bloom syndrome (PMID: 7585968, 17407155). ClinVar contains an entry for this variant (Variation ID: 42078). Experimental studies have shown that this missense change causes loss of BLM helicase and ATPase activity, defective nuclear foci formation, and decreased cellular responses to DNA damage (PMID: 9840919, 11399766, 10069810, 28877996). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000034904 SCV000918657 pathogenic Bloom syndrome 2018-10-25 criteria provided, single submitter clinical testing Variant summary: BLM c.3164G>C (p.Cys1055Ser) results in a non-conservative amino acid change located in the ATP-dependent DNA helicase RecQ, zinc-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 243968 control chromosomes (gnomAD). c.3164G>C has been reported in the literature in individuals affected with Bloom Syndrome (Ellis_1995, German_2007). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal helicase and DNA dependent ATPase activities (Neff_1999). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics RCV000034904 SCV001139712 pathogenic Bloom syndrome 2019-05-28 criteria provided, single submitter clinical testing

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