ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.1642C>T (p.Gln548Ter) (rs200389141)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000574676 SCV000672923 pathogenic Hereditary cancer-predisposing syndrome 2017-04-04 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)
Counsyl RCV000144577 SCV000678009 likely pathogenic Bloom syndrome 2014-01-23 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000115284 SCV000331817 pathogenic not provided 2015-11-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000144577 SCV000893388 pathogenic Bloom syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000115284 SCV000149193 pathogenic not provided 2017-05-10 criteria provided, single submitter clinical testing This variant is denoted BLM c.1642C>T at the cDNA level and p.Gln548Ter (Q548X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant is a common founder variant among Slavic populations, reported in up to 1% of breast cancer cases in Russia (Sokolenko 2012). While this variant has been estimated by Prokofyeva et al. (2013) to increase the breast cancer risk two- to five-fold in meta-analyses (p=0.03), Anisimenko et al. (2014) did not identify a statistically significant difference in observations among non-selected breast cancer cases and healthy controls. Of note, this variant has also been reported in the compound heterozygous state in multiple individuals diagnosed with Bloom syndrome (German 2007, Classen 2013). Based on currently available evidence, we consider p.Gln548Ter to be pathogenic. 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. If a BLM mutation carrier'spartner also has a BLM mutation, the risk to have a child with Bloom syndrome is 25% with each pregnancy.
GeneKor MSA RCV000574676 SCV000821708 pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000144577 SCV000915700 pathogenic Bloom syndrome 2018-08-15 criteria provided, single submitter clinical testing The BLM c.1642C>T (p.Gln548Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Gln548Ter variant has been identified in a total of eight individuals with Bloom syndrome, including in four in a homozygous state and in four in a compound heterozygous state (German et al. 2007; Classen et al. 2013; Vojtková et al. 2016; Suspitsin et al. 2017). The compound heterozygotes all carry a second null variant in trans including one deletion, one splice variant and two stop-gained variants. The p.Gln548Ter variant was found to segregate with disease in a two generation family. The p.Gln548Ter variant was reported in a heterozygous state in 32 of 8809 controls and is noted to be a founder variant in the Slavic population (Antczak et al. 2013; Bogdanova et al. 2015). The variant is reported at a frequency of 0.00033 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence and the potential impact of stop-gained variants, the p.Gln548Ter variant is classified as pathogenic for Bloom syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000144577 SCV000694473 pathogenic Bloom syndrome 2016-06-03 criteria provided, single submitter clinical testing Variant summary: The BLM c.1642C>T (p.Gln548X) variant results in a premature termination codon, predicted to cause a truncated or absent BLM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2207_2212delinsTAGATTC). This variant was also found in 27/124630 control chromosomes at a frequency of 0.0002166, which does not exceed the estimated maximal expected allele frequency of a pathogenic BLM variant (0.0035355). This variant has been reported in three patients with Bloom syndrome, two were known to be compound heterozygotes with another deleterious variant. The variant is also known to confer risk for breast and other types of cancer. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000144577 SCV000543355 pathogenic Bloom syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln548*) in the BLM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs200389141, ExAC 0.03%). This variant has been reported in the literature as a recurring founder mutation in individuals with Bloom syndrome (PMID: 17407155, 23552953). This variant has also been reported in individuals with breast, prostate and colorectal cancer (PMID: 24096176, 23225144, 25399228, 26358404). ClinVar contains an entry for this variant (Variation ID: 127478). Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000144577 SCV000838961 pathogenic Bloom syndrome 2018-07-02 criteria provided, single submitter clinical testing
Pathway Genomics RCV000144577 SCV000189877 pathogenic Bloom syndrome 2014-07-24 no assertion criteria provided clinical testing

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