Submissions for variant NM_000057.4(BLM):c.2662+2T>C

dbSNP: rs1567052324

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700888	SCV000829665	likely pathogenic	Bloom syndrome	2018-06-25	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 13 of the BLM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). This variant has not been reported in the literature in individuals with BLM-related disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000700888	SCV002600389	likely pathogenic	Bloom syndrome	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: BLM c.2662+2T>C 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. Multiple computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site while one predicts this site is weakened. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250892 control chromosomes. c.2662+2T>C has been reported in the literature in heterozygous individuals affected with Pheochromocytoma and Cancer (Gieldon_2019, Nassar_2020). These data indicate that the variant may be associated with disease, although it is unclear whether heterozygous carriers of loss-of-function BLM variants are at elevated risk of cancer (Kluzniak_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV004026532	SCV005022687	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-20	criteria provided, single submitter	clinical testing	The c.2662+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 12 in the BLM gene. 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.
Natera, Inc.	RCV000700888	SCV002088100	likely pathogenic	Bloom syndrome	2021-02-16	no assertion criteria provided	clinical testing