ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115305 SCV000149214 pathogenic not provided 2014-01-14 criteria provided, single submitter clinical testing Single pathogenic variants in BLM have only recently been described in association with cancer predisposition and the risks are not well understood. This mutation is denoted BLM IVS16+2delT or c.3210+2delT and consists of a deletion of one nucleotide substitution at the +2 position of intron 16 of the BLM gene. The normal sequence, with the base that is deleted in brackets, is AAGg[delt]aaaaaaag, where the capital letters are exonic and lowercase are intronic. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the currently available information, we consider BLM c.3210+2delT to be a pathogenic variant. A single pathogenic variant in this gene has been estimated to increase the risk of female breast cancer and colon cancer although there are conflicting reports. A recent meta-analysis estimated the odds ratio for breast cancer to be 2.5 (Sokolenko 2012) which translates to a lifetime risk of approximately 30%. Approximately 1% of individuals of Ashkenazi Jewish descent are carriers of the BLM founder pathogenic variant, c.2207_2212delinsTAGATTC (Ellis 1998). A 2.5-fold increased risk of colon cancer has been described in individuals carrying this specific mutation which amounts to approximately 13% lifetime risk (Gruber 2002). Of note, Cleary et al (2003) did not find evidence of increased cancer risk in carriers of this BLM founder pathogenic variant. Bloom syndrome is an autosomal recessive condition caused by two mutations (one in each copy of the gene) in the BLM gene and is characterized by severe growth deficiency, skin erythema, hypersensitivity to the sun, male infertility and female subfertility, immunodeficiency, and high risk for various types of cancer. When two individuals with known pathogenic variants in this gene have children, the risk to have a child with Bloom syndrome is 25% with each pregnancy.
Invitae RCV000628687 SCV000749593 likely pathogenic Bloom syndrome 2018-12-17 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 not been reported in the literature in individuals with BLM-related disease. 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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