Submissions for variant NM_000057.4(BLM):c.98+1G>T

dbSNP: rs750293380

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Fulgent Genetics, Fulgent Genetics	RCV000410622	SCV000893387	pathogenic	Bloom syndrome	2021-12-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410622	SCV000916682	pathogenic	Bloom syndrome	2021-12-21	criteria provided, single submitter	clinical testing	Variant summary: BLM c.98+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. These predictions are supported by RT-PCR studies that showed exon 2 skipping, though the data was not available for review (German_2007). The variant allele was found at a frequency of 1.3e-05 in 230636 control chromosomes (gnomAD). c.98+1G>T has been reported in the literature in an individual affected with Bloom Syndrome (German_2007). A different variant at the same location (c.98+1G>A) has also been implicated in Bloom Syndrome. Four other ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000410622	SCV000940882	pathogenic	Bloom syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 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 (rs750293380, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with clinical features of Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 370200). Studies have shown that disruption of this splice site results in exon 2 skipping and activation of a cryptic splice site 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	RCV001019785	SCV001181189	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-30	criteria provided, single submitter	clinical testing	The c.98+1G>T pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the BLM gene. This alteration has been reported in a compound heterozygous state with the Ashkenazi founder mutation (c.2207_2212delinsTAGATTC) in a child with Bloom syndrome (German J et al. Hum. Mutat. 2007 Aug;28(8):743-53). 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV000410622	SCV002060232	likely pathogenic	Bloom syndrome	2021-11-19	criteria provided, single submitter	clinical testing	NM_000057.3(BLM):c.98+1G>T is a canonical splice site variant classified as likely pathogenic in the context of Bloom syndrome. c.98+1G>T has been observed in a case with relevant disease (PMID: 17407155). Functional assessments of this variant are available in the literature (PMID: 17407155). c.98+1G>T has been observed in population frequency databases (gnomAD: NFE 0.003%). In summary, NM_000057.3(BLM):c.98+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.
Baylor Genetics	RCV000410622	SCV004210862	pathogenic	Bloom syndrome	2023-08-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477906	SCV004222513	pathogenic	not provided	2023-08-28	criteria provided, single submitter	clinical testing	The BLM c.98+1G>T variant disrupts a canonical splice-donor site and interferes with normal BLM mRNA splicing. This variant has been reported in the published literature in an individual with Bloom syndrome (PMID: 17407155 (2007)). It has also been seen in an individual with acute lymphoblastic leukemia (PMID: 34308104 (2021)). RNA analysis showed that the exon was skipped, which excludes the initiator methionine from the transcript, however further research is needed (PMID: 17407155 (2007)). The frequency of this variant in the general population, 0.000013 (3/230636 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.