Submissions for variant NM_000057.4(BLM):c.1934A>G (p.Gln645Arg)

dbSNP: rs377563699

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463716	SCV000543382	uncertain significance	Bloom syndrome	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 645 of the BLM protein (p.Gln645Arg). This variant is present in population databases (rs377563699, gnomAD 0.04%). This missense change has been observed in individual(s) with hematological malignancy (PMID: 33850299). ClinVar contains an entry for this variant (Variation ID: 405318). 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%. 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	RCV000569839	SCV000672959	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-05	criteria provided, single submitter	clinical testing	The p.Q645R variant (also known as c.1934A>G), located in coding exon 7 of the BLM gene, results from an A to G substitution at nucleotide position 1934. The glutamine at codon 645 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics	RCV000463716	SCV001139700	uncertain significance	Bloom syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821233	SCV002068655	uncertain significance	not specified	2019-02-27	criteria provided, single submitter	clinical testing
GeneDx	RCV002244930	SCV002513089	uncertain significance	not provided	2024-07-23	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33850299, 28944238)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002244930	SCV004222442	uncertain significance	not provided	2024-10-29	criteria provided, single submitter	clinical testing	The BLM c.1934A>G (p.Gln645Arg) variant has been reported in the published literature in an individual with colorectal cancer (PMID: 28944238 (2017)) and in a cohort of individuals with multiple cancers who also had hematological disorders (PMID: 33850299 (2021)). The frequency of this variant in the general population, 0.00036 (9/24868 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.