ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.3558+1G>T (rs148969222)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205550 SCV000260243 pathogenic Bloom syndrome 2019-12-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 18. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant has been reported to co-occur with another pathogenic variant in an individual with Bloom syndrome (Invitae), as well as in individuals affected with breast cancer and colorectal cancer (PMID: 24733792, 26358404). ClinVar contains an entry for this variant (Variation ID: 220019). A different sequence change at this nucleotide (c.3558+1G>A) has been reported in homozygosity in an individual affected with Bloom syndrome (PMID: 17407155). This indicates that this nucleotide is important for BLM protein function. Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000572028 SCV000672882 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-17 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Illumina Clinical Services Laboratory,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.
Counsyl RCV000205550 SCV000486584 likely pathogenic Bloom syndrome 2019-07-11 no assertion criteria provided clinical testing

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