Submissions for variant NM_000057.4(BLM):c.3558+1G>T

gnomAD frequency: 0.00006  dbSNP: rs148969222

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205550	SCV000260243	pathogenic	Bloom syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 18 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 (rs148969222, gnomAD 0.008%). Disruption of this splice site has been observed in individuals with Bloom syndrome (PMID: 17407155; Invitae). ClinVar contains an entry for this variant (Variation ID: 220019). Studies have shown that disruption of this splice site results in exon 18 skipping 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	RCV000572028	SCV000672882	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	The c.3558+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 17 of the BLM gene. This variant has been detected in a woman diagnosed with bilateral breast cancer with a family history of breast, ovarian, and colorectal cancers (Kurian AW et al. J. Clin. Oncol. 2014 Jul;32:2001-9). Another study detected this alteration in a proband diagnosed with colorectal cancer at age 29 who also had a family history of colorectal cancer (de Voer RM et al. Sci Rep, 2015 Sep;5:14060). In a case-control study, this variant was identified in 1/2000 individuals with breast or ovarian cancer and in 0/1997 cancer-free controls (Thompson ER et al. J. Clin. Oncol. 2016 May;34:1455-9). This nucleotide position is highly conserved in available vertebrate species. 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.
Illumina Laboratory Services, Illumina	RCV000205550	SCV000914703	uncertain significance	Bloom syndrome	2017-05-03	criteria provided, single submitter	clinical testing	The BLM c.3558+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.3558+1G>T variant has been reported in at least three studies in which it is found in a heterozygous state in a total of five individuals with Bloom syndrome including two individuals evaluated for cancer predisposition syndromes and three individuals undergoing routine carrier screening (Kurian et al. 2014; de Voer et al. 2015; Perreault-Micale et al. 2015). Though functional studies of the c.3885+1G>T variant were not available, RNA analysis has suggested an alternate substitution at the same position, c.3885+1G>A, identified in a homozygous state in a single individual with Bloom syndrome, leads to aberrant splicing (German et al. 2007). The c.3885+1G>T variant was absent from at least 532 controls but is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Genome Aggregation Database. The evidence for this variant is limited. Based on the limited evidence and the potential impact of splice donor variants, the c.3558+1G>T variant is classified as a variant of unknown significance but suspicious for pathogenicity for Bloom syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Revvity Omics, Revvity	RCV000205550	SCV002016615	pathogenic	Bloom syndrome	2021-12-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000205550	SCV002060340	likely pathogenic	Bloom syndrome	2021-11-03	criteria provided, single submitter	clinical testing	NM_000057.3(BLM):c.3558+1G>T is a canonical splice variant classified as likely pathogenic in the context of Bloom syndrome. c.3558+1G>T has been observed in cases with relevant disease (PMID: Hopman_2013_(no PMID; article). Functional assessments of this variant are not available in the literature. c.3558+1G>T has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, NM_000057.3(BLM):c.3558+1G>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease and is predicted to disrupt protein function. Please note: this variant was assessed in the context of healthy population screening.
GeneDx	RCV001723775	SCV002538772	pathogenic	not provided	2022-06-21	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); This variant is associated with the following publications: (PMID: 26358404, 26247052, 24733792, 34767783, 34352413)
Baylor Genetics	RCV000205550	SCV004210841	pathogenic	Bloom syndrome	2023-10-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001723775	SCV004222483	pathogenic	not provided	2022-11-10	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-donor site and interferes with normal BLM mRNA splicing. The frequency of this variant in the general population, 0.000039 (5/128912 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 36315097 (2022), 26786923 (2016), 24733792 (2014)) and colorectal cancer (PMIDs: 34767783 (2022), 26358404 (2015)). Based on the available information, this variant is classified as pathogenic.
GenomeConnect - Invitae Patient Insights Network	RCV000205550	SCV001749479	not provided	Bloom syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 11-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723775	SCV001951358	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723775	SCV001968556	pathogenic	not provided		no assertion criteria provided	clinical testing