Submissions for variant NM_000057.4(BLM):c.3875-2A>G

gnomAD frequency: 0.00001  dbSNP: rs150421256

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409613	SCV000486224	likely pathogenic	Bloom syndrome	2016-04-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409613	SCV000814881	uncertain significance	Bloom syndrome	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 20 of the BLM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 2 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs150421256, gnomAD 0.002%). 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: 370814). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 21 (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics	RCV000409613	SCV000838987	likely pathogenic	Bloom syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001021334	SCV001182937	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-04-09	criteria provided, single submitter	clinical testing	The c.3875-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 20 of the BLM gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor 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.
CeGaT Center for Human Genetics Tuebingen	RCV001090940	SCV001246733	likely pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000409613	SCV004210910	pathogenic	Bloom syndrome	2023-03-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000409613	SCV002090620	likely pathogenic	Bloom syndrome	2021-04-23	no assertion criteria provided	clinical testing