Submissions for variant NM_000057.4(BLM):c.2193+1_2193+9del

dbSNP: rs1060500652

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000469408	SCV000543397	pathogenic	Bloom syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 9 of the BLM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 405328). Studies have shown that disruption of this splice site results in skipping of exon 9 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000469408	SCV000694476	likely pathogenic	Bloom syndrome	2016-08-26	criteria provided, single submitter	clinical testing	Variant summary: The BLM c.2193+1_2193+9delGTAAGTTAT variant involves the deletion of 9 intronic nucleotides including the highly conserved nucleotides at the +1 and +2 positions. One in silico tool predicts a damaging outcome for this variant and 5/5 in silico splicing prediction tools via Alamut predict the complete loss of a canonical splice acceptor site. This variant is absent in 120322 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, due to the potential impact of this variant on splicing, it is classified as likely pathogenic.
Counsyl	RCV000469408	SCV000790435	likely pathogenic	Bloom syndrome	2017-03-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002429478	SCV002728646	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-14	criteria provided, single submitter	clinical testing	The c.2193+1_2193+9delGTAAGTTAT intronic variant results from a deletion of 9 nucleotides after coding exon 8 of the BLM gene. The deleted region includes the canonical splice donor site which is highly conserved. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
GeneDx	RCV003441865	SCV004170364	likely pathogenic	not provided	2023-10-08	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17407155)
Baylor Genetics	RCV000469408	SCV004210858	pathogenic	Bloom syndrome	2023-09-16	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000469408	SCV002088038	likely pathogenic	Bloom syndrome	2017-11-07	no assertion criteria provided	clinical testing