Submissions for variant NM_000057.4(BLM):c.2702G>A (p.Cys901Tyr)

dbSNP: rs758311406

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001224607	SCV001396819	uncertain significance	Bloom syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 901 of the BLM protein (p.Cys901Tyr). This variant is present in population databases (rs758311406, gnomAD 0.0009%). This missense change has been observed in individual(s) with Bloom syndrome (PMID: 11281456, 17407155). ClinVar contains an entry for this variant (Variation ID: 952488). 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: 17878217). 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.
GeneDx	RCV002225809	SCV002504208	likely pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced ATPase and helicase activity by in vitro assay (Guo et al., 2007); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26788541, 17878217, 17407155, 10965492, 11281456, 32704157, 33357470)
Ambry Genetics	RCV002429952	SCV002742145	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-07-08	criteria provided, single submitter	clinical testing	The p.C901Y variant (also known as c.2702G>A), located in coding exon 13 of the BLM gene, results from a G to A substitution at nucleotide position 2702. The cysteine at codon 901 is replaced by tyrosine, an amino acid with highly dissimilar properties. An individual diagnosed with Bloom Syndrome was identified to carry this alteration in the homozygous state (German J et al. Hum Mutat, 2007 Aug;28:743-53). This alteration showed strong reduction in helicase and ATPase activity, and deficient binding to DNA, but no deficiency in ATP binding or strand annealing capabilities (Guo RB et al. Nucleic Acids Res, 2007 Sep;35:6297-310). Additionally, internal structural analysis of this variant shows that it is highly destabilizing to the local structure (Ambry internal data, Chen X et al. Elife, 2021 03;10:) and it is also predicted to be deleterious by in silico analysis. This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001224607	SCV004039131	likely pathogenic	Bloom syndrome	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: BLM c.2702G>A (p.Cys901Tyr) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Helicase, C-terminal (IPR001650) 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 4e-06 in 251442 control chromosomes (gnomAD). c.2702G>A has been reported in the literature in an individual affected with Bloom Syndrome (Ellis_2001, German_2007). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding the variant results in a loss of ATPase, helicase, and DNA binding activity (Guo_2007). The following publications have been ascertained in the context of this evaluation (PMID: 11281456, 17407155, 17878217). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely pathogenic (n=2) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.