Submissions for variant NM_000057.4(BLM):c.368A>G (p.Gln123Arg)

gnomAD frequency: 0.00005  dbSNP: rs371223446

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115311	SCV000149220	uncertain significance	not provided	2014-03-03	criteria provided, single submitter	clinical testing	Single mutation 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.368A>G at the cDNA level, p.Gln123Arg (Q123R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Gln123Arg was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution and may affect protein integrity. BLM Gln123Arg occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. On 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	RCV000473466	SCV000543326	uncertain significance	Bloom syndrome	2025-01-30	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 123 of the BLM protein (p.Gln123Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with prostate cancer (PMID: 25111073). ClinVar contains an entry for this variant (Variation ID: 127503). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Fulgent Genetics, Fulgent Genetics	RCV000473466	SCV000896478	uncertain significance	Bloom syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001020887	SCV001182428	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-14	criteria provided, single submitter	clinical testing	The p.Q123R variant (also known as c.368A>G), located in coding exon 2 of the BLM gene, results from an A to G substitution at nucleotide position 368. The glutamine at codon 123 is replaced by arginine, an amino acid with highly similar properties. This variant segregated with disease in three individuals from a familial prostate cancer family; however, three variants in other genes also co-segregated with prostate cancer in this family (Johnson AM et al. Prostate 2014 Oct;74(14):1371-8). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000115311	SCV002010752	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800289	SCV005422313	uncertain significance	not specified	2024-10-14	criteria provided, single submitter	clinical testing	Variant summary: BLM c.368A>G (p.Gln123Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251252 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.368A>G has been reported in the literature in individuals affected with Cancer (Johnson_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25111073). ClinVar contains an entry for this variant (Variation ID: 127503). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000473466	SCV001456638	uncertain significance	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing