ClinVar Miner

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

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000115284 SCV000331817 pathogenic not provided 2015-11-25 criteria provided, single submitter clinical testing
Invitae RCV000144577 SCV000543355 pathogenic Bloom syndrome 2019-12-27 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.
Ambry Genetics RCV000574676 SCV000672923 pathogenic Hereditary cancer-predisposing syndrome 2018-07-12 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
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.
GeneKor MSA RCV000574676 SCV000821708 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This is a nonsense variant that creates a premature stop signal at codon 548 of the BLM protein. It is expected to result in an absent or disrupted protein product. This variant is a common founder mutation among Slavik populations, reported in up to 1% of breast cancer cases in Russia (PMID: 21815139). A meta-analysis study of this mutation has estimated the risk of breast cancer in carriers of this variant to be two to five times higher (PMID: 23225144).
Mendelics RCV000144577 SCV000838961 pathogenic Bloom syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000144577 SCV000893388 pathogenic Bloom syndrome 2018-10-31 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.
Broad Institute Rare Disease Group,Broad Institute RCV000144577 SCV001164401 pathogenic Bloom syndrome 2018-12-03 criteria provided, single submitter research The homozygous p.Gln548Ter variant in BLM was identified by our study in one individual with Bloom syndrome. This variant has been identified in 0.03294% (41/124452) of European (non-Finnish) chromosomes by the Genome Aggregation Databse (gnomAD, http://gnomad.broadinsitute.org; dbSNP rs200389141). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported in the literature in the compound heterozygous state, with at least one variant reported pathogenic or likely pathogenic in ClinVar (Variation ID: 127491), in at least three individuals with Bloom syndrome (PMID: 17407155, 23552953). This nonsense variant leads to a premature termination codon at position 548, which is predicted to lead to a truncated or absent protein. Loss of function of the BLM gene is an established disease mechanism for autosomal recessive Bloom syndrome, and this is a loss of function variant. This variant has been reported pathogenic in ClinVar (Variation ID: 127478). In summary, the p.Gln548Ter variant is pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PVS1 (Richards 2015).
Myriad Women's Health, Inc. RCV000144577 SCV001194136 pathogenic Bloom syndrome 2019-12-20 criteria provided, single submitter clinical testing NM_000057.3(BLM):c.1642C>T(Q548*) is classified as pathogenic in the context of Bloom syndrome. Sources cited for classification include the following: PMID 17407155 and 28611551. Classification of NM_000057.3(BLM):c.1642C>T(Q548*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Pathway Genomics RCV000144577 SCV000189877 pathogenic Bloom syndrome 2014-07-24 no assertion criteria provided clinical testing
Counsyl RCV000144577 SCV000678009 pathogenic Bloom syndrome 2019-06-10 no assertion criteria provided clinical testing

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