Submissions for variant NM_000057.4(BLM):c.3751G>C (p.Glu1251Gln)

gnomAD frequency: 0.00002  dbSNP: rs587779888

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115312	SCV000149221	uncertain significance	not provided	2019-02-19	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); Observed in an individual undergoing multi-gene panel testing for personal history of cancer (Mandelker 2017); This variant is associated with the following publications: (PMID: 28873162)
Invitae	RCV000699350	SCV000828056	pathogenic	Bloom syndrome	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1251 of the BLM protein (p.Glu1251Gln). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587779888, 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: 127504). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 19 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001021051	SCV001182616	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	clinical testing	The p.E1251Q variant (also known as c.3751G>C), located in coding exon 18 of the BLM gene, results from a G to C substitution at nucleotide position 3751. The amino acid change results in glutamic acid to glutamine at codon 1251, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 18, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this 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.
Sema4, Sema4	RCV001021051	SCV002532544	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-03	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000699350	SCV002798192	uncertain significance	Bloom syndrome	2022-01-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000699350	SCV002090604	uncertain significance	Bloom syndrome	2019-03-15	no assertion criteria provided	clinical testing