Submissions for variant NM_000057.4(BLM):c.4000_4004del (p.Arg1334fs)

dbSNP: rs1057516261

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412153	SCV000623327	likely pathogenic	Bloom syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1334Glufs*11) in the BLM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the BLM protein. This variant is not present in population databases (gnomAD no frequency). 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: 370136). This variant disrupts the nuclear localization signal (NLS) and the topoisomerase I (TOP1) domain of BLM protein, which are critical for BLM localization to the nucleus and TOP1-mediated RNA:DNA unwinding (PMID: 27657136, 9388480, 10569803). While functional studies have not been performed to directly test the effect of this variant on BLM protein function, this suggests that disruption of this region of the protein is causative of disease. 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	RCV001021637	SCV001183277	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	The c.4000_4004delAGGAA variant, located in coding exon 20 of the BLM gene, results from a deletion of 5 nucleotides at nucleotide positions 4000 to 4004, causing a translational frameshift with a predicted alternate stop codon (p.R1334Efs*11). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of BLM, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 84 amino acids of the protein. This alteration changes amino acid residues within the nuclear localization signal of the BLM protein (Kaneko H et al. Biochem Biophys Res Commun. 1997 Nov 17;240(2):348-53, Gharibyan V and Youssoufian H. Mol Carcinog. 1999 Dec;26(4):261-73) and amino acid residues involved in the interaction of BLM with topoisomerase I (TOP1) (Tangeman L et al. Genes (Basel). 2016 Sep 21;7(9)). However, the exact functional impact of this alteration on BLM activity is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Revvity Omics, Revvity	RCV000412153	SCV002022045	likely pathogenic	Bloom syndrome	2021-01-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000412153	SCV005058122	pathogenic	Bloom syndrome	2024-03-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000412153	SCV000485373	likely pathogenic	Bloom syndrome	2015-11-24	no assertion criteria provided	clinical testing