Submissions for variant NM_000057.4(BLM):c.3991A>G (p.Arg1331Gly)

gnomAD frequency: 0.00010  dbSNP: rs150631940

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115315	SCV000149224	uncertain significance	not provided	2022-01-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: behaves similarly to wild-type in response to a DNA-damaging agent (Mirzaei 2012); This variant is associated with the following publications: (PMID: 23129629)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000536540	SCV000623326	uncertain significance	Bloom syndrome	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1331 of the BLM protein (p.Arg1331Gly). This variant is present in population databases (rs150631940, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 127507). 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.
Mendelics	RCV000536540	SCV000838988	uncertain significance	Bloom syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000536540	SCV000898549	uncertain significance	Bloom syndrome	2021-03-30	criteria provided, single submitter	clinical testing	BLM NM_000057 exon 21 p.Arg1331Gly (c.3991A>G):This variant has not been reported in the literature but is present in 5/24038 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs150631940). This variant is present in ClinVar (Variation ID:127507). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. Functional studies suggest that this variant may not impact the protein (Mirzaei 2012 PMID:231296269). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Ambry Genetics	RCV001021594	SCV001183230	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-06	criteria provided, single submitter	clinical testing	The p.R1331G variant (also known as c.3991A>G), located in coding exon 20 of the BLM gene, results from an A to G substitution at nucleotide position 3991. The arginine at codon 1331 is replaced by glycine, an amino acid with dissimilar properties. In a study using a humanized yeast model, this alteration was found to perform similar to wildtype when exposed to a DNA-damaging agent (Mirzaei H et al. Proc. Natl. Acad. Sci. U.S.A., 2012 Nov;109:19357-62). This alteration was identified in an individual diagnosed with colorectal cancer (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251984	SCV002523555	uncertain significance	See cases	2020-02-24	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, BP4
Fulgent Genetics, Fulgent Genetics	RCV000536540	SCV002789266	uncertain significance	Bloom syndrome	2021-11-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115315	SCV004222495	uncertain significance	not provided	2024-01-25	criteria provided, single submitter	clinical testing	The BLM c.3991A>G (p.Arg1331Gly) variant has been reported in the published literature in an individual with breast cancer (PMID: 35264596 (2022)) and in an individual with colorectal cancer (PMID: 28944238 (2017)). In a functional study, this variant showed a similar sensitivity to wild type when exposed to a DNA damaging agent (PMID: 23129629)). The frequency of this variant in the general population, 0.00024 (6/24974 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000536540	SCV005402391	uncertain significance	Bloom syndrome	2024-04-10	criteria provided, single submitter	clinical testing	The BLM c.3991A>G (p.Arg1331Gly) missense change has a maximum subpopulation frequency of 0.024% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function and functional studies have shown this variant does not impact protein function (PMID: 23129629). This variant has not been reported in individuals with Bloom syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.