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

dbSNP: rs367543029

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000569697	SCV000672962	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-14	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; Montenegro MM et al. Mol Genet Genomic Med, 2020 04;8:e1133). 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034904	SCV000749572	pathogenic	Bloom syndrome	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1055 of the BLM protein (p.Cys1055Ser). This variant is present in population databases (rs367543029, gnomAD 0.002%). This missense change has been observed in individuals with Bloom syndrome (PMID: 7585968, 17407155, 35218564). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42078). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BLM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BLM function (PMID: 9840919, 10069810, 11399766, 28877996). For these reasons, this variant has been classified as 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
Revvity Omics, Revvity	RCV000034904	SCV002018395	pathogenic	Bloom syndrome	2020-09-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000569697	SCV002530061	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-08	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000034904	SCV002787346	pathogenic	Bloom syndrome	2024-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000034904	SCV004210906	pathogenic	Bloom syndrome	2023-11-20	criteria provided, single submitter	clinical testing