rs367543013
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000057.4(BLM):c.772_773delCT(p.Leu258GlufsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
BLM
NM_000057.4 frameshift
NM_000057.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.193
Genes affected
BLM (HGNC:1058): (BLM RecQ like helicase) The Bloom syndrome is an autosomal recessive disorder characterized by growth deficiency, microcephaly and immunodeficiency among others. It is caused by homozygous or compound heterozygous mutation in the gene encoding DNA helicase RecQ protein on chromosome 15q26. This Bloom-associated helicase unwinds a variety of DNA substrates including Holliday junction, and is involved in several pathways contributing to the maintenance of genome stability. Identification of pathogenic Bloom variants is required for heterozygote testing in at-risk families. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-90750035-ACT-A is Pathogenic according to our data. Variant chr15-90750035-ACT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000657 AC: 10AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000321 AC: 8AN: 249258Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135098
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461848Hom.: 0 AF XY: 0.00000825 AC XY: 6AN XY: 727220
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GnomAD4 genome 0.0000657 AC: 10AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74320
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bloom syndrome Pathogenic:9
| Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 06, 2024 | The BLM c.772_773del (p.Leu258GlufsTer7) change deletes two nucleotides to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been observed in an individual with Bloom syndrome (PMID: 17407155). This variant has a maximum subpopulation frequency of 0.02% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). In summary, this variant meets criteria to be classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 12, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 24, 2017 | Variant summary: The BLM c.772_773delCT (p.Leu258Glufs) 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 (p.Tyr736fs) and c.1642C>T (p.Gln548X)). One in silico tool predicts a damaging outcome for this variant. This variant was found in 5/119222 control chromosomes at a frequency of 0.0000419, which does not exceed the estimated maximal expected allele frequency of a pathogenic BLM variant (0.0035355). The variant has been reported in at least one homozygous affected individual in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as "pathogenic." - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 19, 2024 | This sequence change creates a premature translational stop signal (p.Leu258Glufs*7) 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 (rs760209332, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Bloom syndrome and breast and ovarian cancer (PMID: 17407155, 24448499, 28724667). This variant is also known as c.768_769del, p.D256fs. ClinVar contains an entry for this variant (Variation ID: 42092). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PVS1+PM2_Supporting+PM3_Strong+PP1+PP4 - |
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 04, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 20, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 07, 2022 | 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; Identified in the heterozygous state in individuals with breast, ovarian, or colorectal cancer (Kanchi et al., 2014; Sun et al., 2017; Huang et al., 2018); This variant is associated with the following publications: (PMID: 26247052, 17407155, 24448499, 28724667, 29625052, 29783825, 29478780, 31721094) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 06, 2023 | This 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 has been reported in individuals with breast cancer (PMID: 36315097 (2022), 28724667 (2017)), rectal cancer (PMID: 29625052 (2018)), colorectal cancer (PMID: 29478780 (2018)), lung cancer (PMID: 35273153 (2022), 31721094 (2020)), and astrocytoma (PMID: 32783018 (2019), 31133068 (2019)). This variant has also been observed in individuals with Bloom Syndrome (PMID: 29783825 (2018), 17407155 (2007)). The frequency of this variant in the general population, 0.00016 (4/24446 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 29, 2024 | The c.772_773delCT pathogenic mutation, located in coding exon 2 of the BLM gene, results from a deletion of two nucleotides at nucleotide positions 772 to 773, causing a translational frameshift with a predicted alternate stop codon (p.L258Efs*7). This mutation has been reported in the homozygous and compound heterozygous states in patients with Bloom syndrome (German J et al. Hum Mutat, 2007 Aug;28:743-53; Wu ML et al. Zhonghua Er Ke Za Zhi, 2018 May;56:373-376). This mutation has also been reported in a patient with ovarian cancer (Kanchi KL et al. Nat Commun, 2014;5:3156). 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. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at