ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2207_2212delinsTAGATTC (p.Tyr736fs) (rs113993962)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000058933 SCV000149199 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing Conservative substitution of one neutral polar amino acid for another at a position that is well conserved throughout evolution and is not located in a known functional domain; In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function; Haplotype analysis by Ellis et al. (1998) observed that this variant was present on all chromosomes carrying the BLM Ashkenazi Jewish founder mutation, c.2207_2212delATCTGAinsTAGATTC; Not been reported outside of the Ashkenazi Jewish population.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000005787 SCV000245583 pathogenic Bloom syndrome 2015-01-13 criteria provided, single submitter clinical testing The p.Tyr736LeufsX5 variant in BLM was first reported in 4 Ashkenazi Jewish individuals with Bloom syndrome in the homozygous state (Ellis 1995), and is the most common pathogenic variant in Ashkenazi Jewish individuals in whom it occurs in ~1/111 individuals (Pagan 2002). In vitro functional studies also provide some evidence that the p.Tyr736LeufsX5 variant may impact protein function (Ellis 1995). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 736 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Bloom syndrome in an autosomal recessive manner.
Invitae RCV000005787 SCV000283119 pathogenic Bloom syndrome 2017-12-27 criteria provided, single submitter clinical testing This sequence change deletes 6 and inserts 7 nucleotides in exon 10 of the BLM mRNA (c.2207_2212delinsTAGATTC), causing a frameshift at codon 736. This creates a premature translational stop signal (p.Tyr736Leufs*5) and is expected to result 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 is a well documented pathogenic founder variant in Bloom syndrome individuals of Ashkenazi Jewish ancestry (PMID: 7585968, 9758720). This sequence change is known as the "blm-Ash" mutation and described with a legacy nomenclature as a "6-bp deletion and 7-bp insertion at nt 2281" that is present at a carrier rate of 1/107 unaffected individuals of Ashkenazi Jewish ancestry (PMID: 9758720, 9837821). 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 RCV000562115 SCV000672932 pathogenic Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000005787 SCV000694477 pathogenic Bloom syndrome 2019-10-14 criteria provided, single submitter clinical testing Variant summary: BLM c.2207_2212delinsTAGATTC (p.Tyr736LeufsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 249632 control chromosomes (gnomAD). c.2207_2212delinsTAGATTC has been reported in the literature in multiple individuals (both compound heterozygous and homozygous) affected with Bloom Syndrome in Ashkenazi Jewish or Spanish American ancestry (German_2007). This variant (aka blmAsh in the literature), is a well described pathogenic founder mutation in Ashkenazi Jewish population. At least one publication reports experimental evidence evaluating an impact on protein function. Skin fibroblast cell lines established from a person who was homozygous for this variant (GM08505) exhibit a spontaneous, approximately 10-fold increase in the frequency of SCEs (sister chromatid exchanges) compared to cells from unaffected persons. They also present with quadriradial chromosomes in metaphase spreads, are hypersensitive to genotoxic agent hydroxyurea, and show a delay in activating the DNA damage response after exposure to the topoisomerase poison CPT (Shastri_2015). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000058933 SCV000700669 pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing
Mendelics RCV000005787 SCV000838965 pathogenic Bloom syndrome 2018-07-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000005787 SCV000915701 pathogenic Bloom syndrome 2018-10-19 criteria provided, single submitter clinical testing The BLM c.2207_2212delATCTGAinsTAGATTC (p.Tyr736LeufsTer5) variant is well described in the literature as a founder mutation in the Ashkenazi Jewish (AJ) population, commonly known as 'blmAsh', and accounts for 97% of all pathogenic variants reported in the AJ population (Sanz et al. 2016). The p.Tyr736LeufsTer5 variant results in a frameshift and is predicted to result in premature termination of the protein. Among probands of full or half AJ descent, the p.Tyr736LeufsTer5 variant has been reported in at least 27 individuals in a homozygous state and eight individuals in a compound heterozygous state (Ellis et al. 1995; Ellis et al. 1998; German et al. 2007). Among probands of Spanish American ancestry, the p.Tyr736LeufsTer5 variant has been reported in at least three individuals in a homozygous state, and two individuals in a compound heterozygous state (German et al. 2007). The p.Tyr736LeufsTer5 variant has also been detected in at least 52 parents who were unaffected carriers (Ellis et al. 1998). Control data are unavailable for this variant, and the p.Tyr736LeufsTer5 variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium, in a region with good sequence coverage, and hence is presumed to be rare in the general population. Ellis et al. (1999) report that a SV40-transformed fibroblast cell line, derived from a skin biopsy sample obtained from an individual homozygous for the p.Tyr736LeufsTer5 variant was effectively null for the BLM protein. Based on the collective evidence, the p.Tyr736LeufsTer5 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.
Myriad Women's Health, Inc. RCV000005787 SCV001194205 pathogenic Bloom syndrome 2019-10-18 criteria provided, single submitter clinical testing NM_000057.2(BLM):c.2207_2212del6ins7(Y736Lfs*5) is classified as pathogenic in the context of Bloom syndrome. Sources cited for classification include the following: PMID: 17407155, 7585968, 9837821, and 10090915. Classification of NM_000057.2(BLM):c.2207_2212del6ins7(Y736Lfs*5) 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.
OMIM RCV000005787 SCV000025969 pathogenic Bloom syndrome 2002-09-20 no assertion criteria provided literature only
GeneReviews RCV000005787 SCV000058501 pathogenic Bloom syndrome 2019-02-19 no assertion criteria provided literature only
SNPedia RCV000058933 SCV000090454 not provided not provided no assertion provided not provided
Pathway Genomics RCV000005787 SCV000189875 pathogenic Bloom syndrome 2014-07-24 no assertion criteria provided clinical testing

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