rs1057517030
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000057.4(BLM):βc.1083_1084delβ(p.Cys361Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. C361C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000057.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BLM | NM_000057.4 | c.1083_1084del | p.Cys361Ter | frameshift_variant | 5/22 | ENST00000355112.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BLM | ENST00000355112.8 | c.1083_1084del | p.Cys361Ter | frameshift_variant | 5/22 | 1 | NM_000057.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250536Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135436
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461566Hom.: 0 AF XY: 0.0000248 AC XY: 18AN XY: 727102
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Bloom syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371130). This variant is also known as c.1081_1082delTG. This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 27356891). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Cys361*) 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). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 06, 2016 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 17, 2019 | The c.1083_1084delTG variant, located in coding exon 4 of the BLM gene, results from a deletion of two nucleotides at nucleotide positions 1083 to 1084, causing a translational frameshift with a predicted alternate stop codon (p.C361*). This variant was identified in 1/857 unrelated cases of undefined familial colorectal cancer that were negative for a mutation in a known cancer susceptibility gene for colorectal cancer (CRC) (Dobbins SE et al. Fam. Cancer, 2016 10;15:593-9). This variant was also identified in 1/1006 familial early onset colorectal cancer patients as part of a case-control enrichment analysis that was performed using a publicly available independent cohort of 1006 patients of familial early-onset CRC (CanVar) and the Exome Aggregation Consortium (ExAC) database (Díaz-Gay M et al. Cancers (Basel), 2019 11;3:362). Of note, this alteration is also designated as c.1081_1082delTG in the published literature. 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at