Submissions for variant NM_000057.4(BLM):c.3310G>A (p.Gly1104Ser)

gnomAD frequency: 0.00008  dbSNP: rs141269464

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000229039	SCV000283136	uncertain significance	Bloom syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1104 of the BLM protein (p.Gly1104Ser). This variant is present in population databases (rs141269464, gnomAD 0.01%). 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: 236815). 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 not expected to disrupt BLM protein function with a negative predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV001019902	SCV001181315	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-24	criteria provided, single submitter	clinical testing	The p.G1104S variant (also known as c.3310G>A), located in coding exon 16 of the BLM gene, results from a G to A substitution at nucleotide position 3310. The glycine at codon 1104 is replaced by serine, an amino acid with similar properties. This alteration was identified in 1/1358 non-cancer control individuals in a study looking at cancer predisposition mutations in patients with multiple primary cancers (Pritchard AL et al. PLoS ONE, 2018 Apr;13:e0194098). This amino acid position is 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.
GeneDx	RCV001770187	SCV001992828	uncertain significance	not provided	2019-06-26	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 29641532, 29643063, 23129629)
Sema4, Sema4	RCV001019902	SCV002530138	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488481	SCV004241391	uncertain significance	not specified	2023-12-21	criteria provided, single submitter	clinical testing	Variant summary: BLM c.3310G>A (p.Gly1104Ser) results in a non-conservative amino acid change located in the RQC domain (IPR018982) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 253448 control chromosomes (gnomAD and Pritchard_2018). This frequency is not significantly higher than estimated for a pathogenic variant in BLM causing Bloom Syndrome (4.7e-05 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3310G>A in individuals affected with Bloom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29641532). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000229039	SCV002090544	uncertain significance	Bloom syndrome	2018-10-29	no assertion criteria provided	clinical testing