Submissions for variant NM_000057.4(BLM):c.2822A>G (p.Gln941Arg)

gnomAD frequency: 0.00003  dbSNP: rs762267785

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232781	SCV000283126	uncertain significance	Bloom syndrome	2022-10-13	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 941 of the BLM protein (p.Gln941Arg). This variant is present in population databases (rs762267785, gnomAD 0.003%). 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: 236806). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV001016694	SCV001177678	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-09	criteria provided, single submitter	clinical testing	The p.Q941R variant (also known as c.2822A>G), located in coding exon 13 of the BLM gene, results from an A to G substitution at nucleotide position 2822. The glutamine at codon 941 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Genetic Services Laboratory, University of Chicago	RCV001818554	SCV002066871	uncertain significance	not specified	2021-02-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BLM gene demonstrated a sequence change, c.2822A>G, in exon 14 that results in an amino acid change, p.Gln941Arg. This sequence change has been described in gnomAD with a low population frequency of 0.0014% (dbSNP rs762267785). The p.Gln941Arg change affects a moderately conserved amino acid residue located in a domain of the BLM protein that is known to be functional. The p.Gln941Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with BLM-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Gln941Arg change remains unknown at this time.
GeneDx	RCV004812310	SCV005437531	uncertain significance	not provided	2024-06-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed only in an unaffected control in a case control study of cutaneous melanoma (PMID: 29641532); This variant is associated with the following publications: (PMID: 29641532)
Natera, Inc.	RCV000232781	SCV002088121	uncertain significance	Bloom syndrome	2018-09-18	no assertion criteria provided	clinical testing