ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.3210+2del (rs587779886)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000628687 SCV000749593 likely pathogenic Bloom syndrome 2019-12-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 16 of the BLM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals affected with mesothelioma (PMID: 26556299) and prostate cancer (PMID: 29439820). ClinVar contains an entry for this variant (Variation ID: 127497). 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). 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.
Integrated Genetics/Laboratory Corporation of America RCV000628687 SCV000918655 likely pathogenic Bloom syndrome 2018-10-19 criteria provided, single submitter clinical testing Variant summary: BLM c.3210+2delT 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 212810 control chromosomes (gnomAD). c.3210+2delT has been reported in the literature in individuals affected with (metastatic castration-resistant prostate cancer and mesothelioma with no reported second pathogenic variant (Antonarakis_2018, Schrader_2016)). These report(s) do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics RCV001019262 SCV001180594 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-26 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity

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