Submissions for variant NM_000057.4(BLM):c.2015A>G (p.Gln672Arg)

gnomAD frequency: 0.00001  dbSNP: rs747281324

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169338	SCV000220686	likely pathogenic	Bloom syndrome	2014-09-11	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169338	SCV000623256	likely pathogenic	Bloom syndrome	2023-12-26	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 672 of the BLM protein (p.Gln672Arg). This variant is present in population databases (rs747281324, gnomAD 0.005%). This missense change has been observed in individuals with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 188963). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BLM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BLM function (PMID: 10069810, 10812332, 12444098, 17878217, 22582397, 31253795). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV001014085	SCV001174752	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	The p.Q672R variant (also known as c.2015A>G), located in coding exon 7 of the BLM gene, results from an A to G substitution at nucleotide position 2015. The glutamine at codon 672 is replaced by arginine, an amino acid with highly similar properties. This alteration was reported in two individuals diagnosed with Bloom syndrome (German J et al. Hum. Mutat. 2007 Aug;28:743-53). Functional studies showed that this alteration has reduces the ATP binding, ATPase and helicase activities of the BLM protein and increases sister chromatid exchange and recombination rates in cells (Guo RB et al. Nucleic Acids Res. 2007 Sep;35:6297-310; Neff NF et al. Mol. Biol. Cell. 1999 Mar;10:665-76; Onoda F et al. Mutat. Res. 2000 Apr;459:203-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001310295	SCV001500030	likely pathogenic	not provided	2020-08-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001310295	SCV002046764	likely pathogenic	not provided	2021-03-22	criteria provided, single submitter	clinical testing	This variant has been reported in individuals with Bloom syndrome in the published literature (PMID: 17407155 (2007) and 7585968 (1995)). Functional studies show that this variant is damaging to protein function (PMID: 31253795 (2019), 22582397 (2012), 17878217 (2007), 12444098 (2002), 10812332 (2000), 10069810 (1999)). Predicted to have a damaging effect on the protein. Based on the available information, this variant is classified as likely pathogenic.
Baylor Genetics	RCV000169338	SCV004210836	likely pathogenic	Bloom syndrome	2023-12-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001310295	SCV005325631	likely pathogenic	not provided	2023-08-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced helicase and ATPase activity, impaired nuclear foci formation, and defective chromosomal segregation and protection (Neff et al., 1999; Onoda et al., 2000; Stavropoulos et al., 2002; Guo et al., 2007; Wu et al., 2012; Addis Jones et al., 2019); Observed with a second BLM variant in individuals with Bloom syndrome (German et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9840919, 24816114, 10965492, 22582397, 30044990, 31253795, 17878217, 12444098, 26247052, 7585968, 17407155, 10069810, 10812332)