NM_000057.4:c.2506_2507delAG
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B.
The NM_000057.4(BLM):c.2506_2507delAG(p.Arg836GlyfsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R836R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000057.4 frameshift
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
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000756 AC: 19AN: 251380 AF XY: 0.0000662 show subpopulations
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461798Hom.: 0 AF XY: 0.0000110 AC XY: 8AN XY: 727202 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74318 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
Age Distribution
ClinVar
Submissions by phenotype
Bloom syndrome Pathogenic:6
This sequence change creates a premature translational stop signal (p.Arg836Glyfs*18) in the BLM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). This variant is present in population databases (rs367543024, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 42071). For these reasons, this variant has been classified as Pathogenic. -
- -
The proband, a Hispanic male child from the US-Mexico border, had features of Bloom syndrome including short stature, failure to thrive, microcephaly, a long thin face with coarse facial features, little subcutaneous fat, and multi-pigmented skin lesions. At age 3 the proband developed rhabdomyosarcoma, a tumor type not previously observed in Bloom syndrome. He was found to be homozygous for BLM c.2506_2507delAG variant, a variant previously described in two other individuals, one Mexican and one from New Mexico. Using flanking markers a common homozygous haplotype was revealed in our patient as well as his two affected siblings, suggesting that this variant is a previously unrecognized founder mutation in the Mexican population. -
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
Variant summary: BLM c.2506_2507delAG (p.Arg836GlyfsX18) 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 allele was found at a frequency of 7.6e-05 in 251380 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BLM causing Bloom Syndrome (7.6e-05 vs 0.0035), allowing no conclusion about variant significance. c.2506_2507delAG has been reported in the literature in homozygous and compound heterozygous individuals affected with Bloom Syndrome (e.g. German_2007). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
- -
not provided Pathogenic:2
This frameshift variant alters the translational reading frame of the BLM mRNA and causes the premature termination of BLM protein synthesis. In the published literature, the variant has been reported in individuals affected with advanced cancers (PMID: 29625052 (2018)) and Bloom syndrome with a second pathogenic variant (PMID: 17407155 (2007)). One family study showed the variant segregated with disease (PMID: 33832920 (2021)). Based on the available information, this variant is classified as pathogenic. -
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; This variant is associated with the following publications: (PMID: 35969835, 36087940, 36451132, 29625052, 33832920, 17407155, 34308104, 26247052, 37594403) -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.2506_2507delAG pathogenic mutation, located in coding exon 11 of the BLM gene, results from a deletion of two nucleotides at nucleotide positions 2506 to 2507, causing a translational frameshift with a predicted alternate stop codon (p.R836Gfs*18). This mutation has been reported in the homozygous and compound heterozygous state in patients with Bloom syndrome (German J et al. Hum. Mutat., 2007 Aug;28:743-53). This alteration has also been reported in one individual with cervical squamous cell carcinoma and another individual with liposarcoma (Huang KL et al. Cell, 2018 04;173:355-370.e14). 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. -
- -
BLM-related disorder Pathogenic:1
The BLM c.2506_2507delAG variant is predicted to result in a frameshift and premature protein termination (p.Arg836Glyfs*18). This variant was reported in the homozygous or compound heterozygous state in individuals with Bloom syndrome (German et al. 2007. PubMed ID: 17407155; Sybouts et al. 2021. PubMed ID: 33832920). This variant is reported in 0.055% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in BLM are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at