ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2923del (p.Gln975fs) (rs367543014)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000571923 SCV000672965 pathogenic Hereditary cancer-predisposing syndrome 2017-07-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Counsyl RCV000034902 SCV000486234 pathogenic Bloom syndrome 2016-04-20 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000115301 SCV000336681 pathogenic not provided 2015-10-26 criteria provided, single submitter clinical testing
GeneDx RCV000115301 SCV000149210 pathogenic not provided 2016-09-15 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 c.2923delC at the cDNA level and p.Gln975LysfsX24 (Q975KfsX24) at the protein level. The normal sequence, with the base that is deleted in brackets, is CTAC[C]AAGA. The deletion causes a frameshift, changing a Glutamine to a Lysine at codon 975, and creating a premature stop codon at position 24 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BLM 2923delC has been published as a mutation in association with Bloom syndrome (German 2007). Therefore, we consider this a pathogenic variant, and this individual is a carrier of Bloom syndrome, a recessive condition characterized by short stature, skin changes in response to sun exposure, and increased cancer risk.One variant in the BLM gene has been thought 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. Based on the currently available information, cancer risks associated with this variant, and with single variants the BLM gene in general, remain unclear.
Invitae RCV000034902 SCV000543387 pathogenic Bloom syndrome 2018-11-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln975Lysfs*24) in the BLM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs752505986, ExAC 0.006%). This variant has been reported in the literature in individuals with Bloom syndrome both in the homozygous and the compound heterozygous state (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 42076). Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). For these reasons, this variant has been classified as Pathogenic.

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