rs367543024

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000057.4(BLM):c.2506_2507del(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

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

BLM
NM_000057.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.68

Variant links:

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]

BLM links:

Genome browser will be placed here

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 15-90769536-CAG-C is Pathogenic according to our data. Variant chr15-90769536-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 42071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4 linkuse as main transcript	c.2506_2507del	p.Arg836GlyfsTer18	frameshift_variant	12/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8 linkuse as main transcript	c.2506_2507del	p.Arg836GlyfsTer18	frameshift_variant	12/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251380

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461798

Hom.:

AF XY:

0.0000110

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bloom syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 29, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 16, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Greehey Children's Cancer Research Institute, UT Health San Antonio	Aug 01, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 05, 2021	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

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 11, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 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; This variant is associated with the following publications: (PMID: 29625052, 33832920, 17407155, 26247052) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 23, 2021	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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 14, 2021	- -

BLM-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2023

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over