Submissions for variant NM_000057.4(BLM):c.3397A>G (p.Lys1133Glu)

gnomAD frequency: 0.00015  dbSNP: rs145027663

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115306	SCV000149215	uncertain significance	not provided	2014-02-25	criteria provided, single submitter	clinical testing	Single pathogenic variants in BLM have only recently been described in association with cancer predisposition and the risks are not well understood. This variant is denoted BLM c.3397A>G at the cDNA level, p.Lys1133Glu (K1133E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Lys1133Glu was observed with an allele frequency of 0.1% (5/4396) in African Americans in the NHLBI Exome Sequencing Project, not frequent enough to be considered a polymorphism. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution and is likely to affect protein integrity. BLM Lys1133Glu occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. At a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and with single variants the BLM gene in general, remain unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542140	SCV000623312	uncertain significance	Bloom syndrome	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1133 of the BLM protein (p.Lys1133Glu). This variant is present in population databases (rs145027663, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 127498). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BLM protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect BLM function (PMID: 23129629). 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.
Ambry Genetics	RCV000567551	SCV000672907	likely benign	Hereditary cancer-predisposing syndrome	2019-02-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Sema4, Sema4	RCV000567551	SCV002532389	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-18	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004745185	SCV005349710	uncertain significance	BLM-related disorder	2024-06-21	no assertion criteria provided	clinical testing	The BLM c.3397A>G variant is predicted to result in the amino acid substitution p.Lys1133Glu. To our knowledge, this variant has not been reported in association with disorders in the literature. Functional studies showed that this variant does not significantly affect protein function in response to DNA-damaging agents (Table 1, Mirzaei et al. 2012. PubMed ID: 23129629). This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/127498). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.