ClinVar Miner

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

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Total submissions: 5
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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 The p.C1055S pathogenic mutation (also known as c.3164G>C), located in coding exon 15 of the BLM gene, results from a G to C substitution at nucleotide position 3164. The cysteine at codon 1055 is replaced by serine, an amino acid with dissimilar properties. This mutation has been reported in the literature in both a homozygous and compound heterozygous state in individuals with Bloom syndrome (Ellis NA et al. Cell, 1995 Nov;83:655-66; German J et al. Hum. Mutat., 2007 Aug;28:743-53). Functional studies have also demonstrated that this alteration causes reduced BLM protein expression and lacks detectable helicase and DNA-dependent ATPase activities, which are essential for wild-type interaction of BLM with tp53 in the DNA damage response pathway (Wang XW et al. J. Biol. Chem., 2001 Aug;276:32948-55; Neff NF et al. Mol. Biol. Cell, 1999 Mar;10:665-76). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000034904 SCV000749572 likely pathogenic Bloom syndrome 2020-09-24 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000034904 SCV000918657 pathogenic Bloom syndrome 2020-07-27 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 8e-06 in 248860 control chromosomes. c.3164G>C has been reported in the literature in multiple individuals affected with Bloom Syndrome (example, Ellis_1995, German_2007). These data indicate that the variant is very 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). Three 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 (n=2)/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
Centogene AG - the Rare Disease Company RCV000034904 SCV001426546 pathogenic Bloom syndrome criteria provided, single submitter clinical testing

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