Submissions for variant NM_000057.4(BLM):c.2074+1G>T

dbSNP: rs367543036

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000034892	SCV000485652	likely pathogenic	Bloom syndrome	2016-01-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034892	SCV000543336	likely pathogenic	Bloom syndrome	2023-06-07	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 42066). Disruption of this splice site has been observed in individual(s) with Bloom syndrome (PMID: 17407155). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 8 of the BLM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034892	SCV002548344	likely pathogenic	Bloom syndrome	2022-05-02	criteria provided, single submitter	clinical testing	Variant summary: BLM c.2074+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: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251216 control chromosomes. c.2074+1G>T has been reported in the literature in at least one individual affected with Bloom Syndrome (German_2007). 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. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.