rs113993962
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000057.4(BLM):c.2207_2212delATCTGAinsTAGATTC(p.Tyr736LeufsTer5) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000057.4 frameshift, missense
Scores
Clinical Significance
Conservation
Publications
- Bloom syndromeInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet, Genomics England PanelApp, ClinGen
- osteosarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- breast cancerInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
- hereditary nonpolyposis colon cancerInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Bloom syndrome Pathogenic:11Other:1
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The BLM c.2207_2212delinsTAGATTC (p.Tyr736LeufsTer5) change results from the deletion of 6 nucleotides and insertion of 7 nucleotides to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense-mediated decay (PVS1). This variant has a maximum subpopulation frequency of 0.38% in gnomAD v2.1.1, where it is primarily found in the Ashkenazi Jewish population (https://gnomad.broadinstitute.org/variant/15-91310152-TATC-T). This variant has been reported in the homozygous and compound heterozygous state in many individuals with Bloom syndrome (PS4, PM3; PMID: 7585968, 9837821, 17407155). It is a well-established pathogenic founder variant in Bloom syndrome which is estimated to be found in 1 of 107 individuals in the Ashkenazi Jewish population (PMID: 9758720). Studies of heterozygous carriers of this variant and colorectal cancer risk have been inconclusive. Gruber et al. found that Ashkenazi Jewish individuals with colorectal cancer harbor this alteration twice as frequently as compared to controls (PMID: 12242432), however Clearly et al. were unable to replicate these findings (PMID: 12702560) and Baris et al. did not find an increased risk for colorectal cancer in heterozygous carriers of this variant (PMID: 18210922). As of May 2021, the National Comprehensive Cancer Network (NCCN) suggests that heterozygous carriers of pathogenic variants in BLM may have an increased risk of colorectal cancer, however the exact risk is not well-established. This alteration is also known as ‘blmAsh’ in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM3. -
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. -
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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. -
The BLM c.2207_2212delinsTAGATTC; p.Tyr736LeufsTer5 variant (also known as BLM(Ash)) is widely reported in the literature in patients with Bloom Syndrome (Bouman 2018, Fiala 2021, Hogan 2018, Huson 2022, Lowery 2018), most commonly in individuals of Ashkenazi Jewish descent (Schayek 2017). This variant is reported in ClinVar database (Variation ID: 5454). The components of this complex variant are reported predominantly in the Ashkenazi Jewish population with an allele frequency of 0.4% (39/10,340 alleles) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by deletion-insertion of seven nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bouman A et al. Bloom syndrome does not always present with sun-sensitive facial erythema. Eur J Med Genet. 2018 Feb. PMID: 29056561. Fiala EM et al. Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors. Nat Cancer. 2021 Mar. PMID: 34308366. Hogan GJ et al. Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification. Clin Chem. 2018 Jul. PMID: 29760218. Huson SM et al. Infantile fibrosarcoma with TPM3-NTRK1 fusion in a boy with Bloom syndrome. Fam Cancer. 2022 Jan. PMID: 33219493. Lowery MA et al. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. J Natl Cancer Inst. 2018 Oct 1. PMID: 29506128. Schayek H et al. Colorectal and Endometrial Cancer Risk and Age at Diagnosis in BLMAsh Mutation Carriers. Isr Med Assoc J. 2017 Jun. PMID: 28647934. -
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. -
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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. -
not provided Pathogenic:6Other:1
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BLM: PVS1, PM2, PP4 -
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18264947, 26788541, 21815139, 24096176, 26277320, 29056561, 29506128, 31816118, 34308366, 34994613, 33219493, 35099000, 7585968) -
The BLM c.2207_2212delinsTAGATTC (p.Tyr736Leufs*5) variant alters the translational reading frame of the BLM mRNA and causes the premature termination of BLM protein synthesis. In the published literature, this variant (also known as the "BLM-Ash" mutation) has been reported in the compound heterozygous or homozygous state in individuals with Bloom syndrome (PMIDs: 37052241 (2023), 17407155 (2007), 10090915 (1999), 9837821 (1998), 7585968 (1995)). This variant in the heterozygous state has also been reported in individuals with colorectal and endometrial cancer (PMIDs: 36744932 (2023), 28647934 (2017), 12702560 (2003), 12242432 (2002)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
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PP4, PM2, PM3, PS3_moderate, PS4_moderate, PVS1 -
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
The c.2207_2212delATCTGAinsTAGATTC pathogenic mutation, located in coding exon 9 of the BLM gene, results from the deletion of 6 nucleotides and insertion of 7 nucleotides at positions 2207 to 2212, causing a translational frameshift with a predicted alternate stop codon (p.Y736Lfs*5). This is a well-established founder mutation in the Ashkenazi Jewish population, reported in individuals with Bloom syndrome in the homozygous or compound heterozygous state, and is referred to as BLMAsh in the literature (Ellis NA et al. Cell. 1995 Nov;83:655-66; Ellis NA et al. Am. J. Hum. Genet. 1998 Dec;63:1685-93; Oddoux C et al. Am. J. Hum. Genet. 1999 Apr;64:1241-3; Bouman A et al. Eur J Med Genet. 2018 Feb;61:94-97). One study found that this alteration was twice as prevalent in Ashkenazi Jewish individuals with colorectal cancer compared to controls (OR=2.45; 95% CI: 1.3-4.8; p=0.0065); however, another study found no significant difference in the carrier frequency of this mutation in individuals with colorectal cancer compared to individuals with other cancers and unaffected controls in an Ashkenazi Jewish population, and when they combined their data with the previous study, they estimated a more modest association with colorectal cancer (OR=1.79; 95% CI 1.17-2.74; p=0.009) (Gruber SB et al. Science. 2002 Sep;297:2013; Cleary SP et al. Cancer Res. 2003 Apr;63:1769-71). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
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BLM-related disorder Pathogenic:1
The BLM c.2207_2212delinsTAGATTC variant is predicted to result in a frameshift and premature protein termination (p.Tyr736Leufs*5). 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 (GeneReviews, https://www.ncbi.nlm.nih.gov/books/NBK1398/). This variant has been reported in numerous individuals of AJ descent in the homozygous and compound heterozygous states (Ellis et al. 1995. PubMed ID: 7585968; Ellis et al. 1998. PubMed ID: 9837821; German et al. 2007. PubMed ID: 17407155). This variant has also been reported in the homozygous and compound heterozygous states in individuals of Spanish American ancestry (German et al. 2007. PubMed ID: 17407155). Functional studies utilizing cells derived from a skin biopsy obtained from an individual homozygous for the c.2207_2212delATCTGAinsTAGATTC (p.Tyr736LeufsTer5) variant showed the variant did not create BLM protein (Ellis et al. 1999. PubMed ID: 10521302). This variant has not been reported in a large population database, indicating it is rare. This variant is reported as pathogenic and likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/5454/). Frameshift variants in BLM are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at