Submissions for variant NM_000057.4(BLM):c.2074+5G>A

dbSNP: rs587779880

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115287	SCV000149196	uncertain significance	not provided	2014-02-26	criteria provided, single submitter	clinical testing	Single pathogenic variants in BLM have only recently been described in association with cancer predisposition and the risks are not well understood. This variant is denoted BLM IVS8+5G>A or c.2074+5G>A and consists of a G>A nucleotide substitution at the +5 position of intron 8 of the BLM gene. Multiple in silico models predict this variant to destroy the nearby natural donor site, and to possibly cause abnormal gene splicing. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM c.2074+5G>A was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant occurs at a position that is highly conserved across species. Based on the currently available information, we consider BLM c.2074+5G>A 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.
Invitae	RCV000812341	SCV000952652	pathogenic	Bloom syndrome	2022-10-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BLM protein in which other variant(s) (p.Gln672Arg) have been determined to be pathogenic (PMID: 10069810, 10812332, 12444098, 17407155, 17878217, 22582397, 31253795). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (Invitae). ClinVar contains an entry for this variant (Variation ID: 127481). This variant has not been reported in the literature in individuals affected with BLM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 8 of the BLM gene. It does not directly change the encoded amino acid sequence of the BLM protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.
Ambry Genetics	RCV002415592	SCV002726357	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-20	criteria provided, single submitter	clinical testing	The c.2074+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 7 in the BLM gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.