Submissions for variant NM_000057.4(BLM):c.2193+1G>A

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Minimum conflict level: Report conflict between different conditions
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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000855680	SCV003264295	likely pathogenic	Bloom syndrome	2022-05-27	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: 694326). 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 9 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).
Ambry Genetics	RCV001014688	SCV001175429	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-02-22	criteria provided, single submitter	clinical testing	The c.2193+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the BLM gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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.
Institute of Human Genetics, University of Goettingen	RCV000855680	SCV000994620	pathogenic	Bloom syndrome	2019-09-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000855680	SCV002088041	likely pathogenic	Bloom syndrome	2021-07-21	no assertion criteria provided	clinical testing

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