rs373525781

Positions:

chr15-90763016-C-T

Variant summary

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

The NM_000057.4(BLM):c.1933C>T(p.Gln645Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000986 in 1,613,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q645Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

BLM
NM_000057.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 1.67

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 15-90763016-C-T is Pathogenic according to our data. Variant chr15-90763016-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 454091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-90763016-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4 linkuse as main transcript	c.1933C>T	p.Gln645Ter	stop_gained	8/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8 linkuse as main transcript	c.1933C>T	p.Gln645Ter	stop_gained	8/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000439

AC:

AN:

250330

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135316

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000970

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

147

AN:

1461222

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

726870

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.000130

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bloom syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 02, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Gln645*) 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 (rs373525781, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with Bloom syndrome and/or breast, ovarian or colorectal cancer (PMID: 17407155, 23028338, 24448499, 27356891). It is commonly reported in individuals of European and North American ancestry (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 454091). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2017	Variant summary: The BLM c.1933C>T (p.Gln645X) 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_2212del6insTAGATTC, p.Tyr736fsX5; c.1968dupG, p.Lys657fsX5). One in silico tool predicts a damaging outcome for this variant. A functional study showed that in two homozygotes with this variant the signal from the mRNA detected in the Bloom Syndrome cell line was less than 20% of the signal detected in the mRNA from a normal cell line (German_2007). This variant was found in 5/124104 control chromosomes at a frequency of 0.0000403, which does not exceed the estimated maximal expected allele frequency of a pathogenic BLM variant (0.0035355). This variant was found in multiple patients with Bloom Syndrome in homozygotes and compound heterozygotes (German_2007). Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 24, 2024	- -

not provided

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 08, 2022	This nonsense variant causes the premature termination of BLM protein synthesis. The frequency of this variant in the general population, 0.000093 (12/128810 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with breast cancer (PMID: 23028338 (2012)), ovarian cancer (PMID: 24448499 (2014), 29625052 (2018)), colorectal cancer (PMID: 27356891 (2016), 29478780 (2018), 29625052 (2018)), Ewing sarcoma (PMID: 28125078 (2017)), and Bloom syndrome with a second pathogenic variant (PMID: 17407155 (2007), 23928670 (2013), 29098565 (2018)). Functional studies also show that this variant fails to suppress a downstream factor that promotes tumorigenesis (PMID: 30044990 (2018)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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; Observed in the heterozygous state in individuals with breast, colon, and other cancers (German et al., 2007; Thompson et al., 2012; Dobbins et al., 2016; Brohl et al., 2017; AlDubayan et al., 2018; Huang et al., 2018); This variant is associated with the following publications: (PMID: 25525159, 26689913, 24448499, 31589614, 29478780, 28125078, 29625052, 23028338, 34136918, 32467344, 26247052, 27356891, 32996068, 17407155) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

BLM-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2024

The BLM c.1933C>T variant is predicted to result in premature protein termination (p.Gln645*). This variant has been reported to be causative for Bloom syndrome (German et al. 2007. PubMed ID: 17407155; Renes et al. 2013. PubMed ID: 23928670; Schoenaker et al. 2018. PubMed ID: 29098565). Additionally, this variant was found to co-segregate with breast cancer in one family (Family 3, Thompson et al. 2012. PubMed ID: 23028338), has been associated with colorectal cancer (Dobbins et al. 2016. PubMed ID: 27356891; Supplementary Table S9, Cases 1743 and 3046, AlDubayan et al. 2018. PubMed ID: 29478780) and was identified in a patient with Ewing sarcoma (Brohl et al. 2017. PubMed ID: 28125078).. This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/454091/). Nonsense variants in BLM are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2023

The p.Q645* pathogenic mutation (also known as c.1933C>T), located in coding exon 7 of the BLM gene, results from a C to T substitution at nucleotide position 1933. This changes the amino acid from a glutamine to a stop codon within coding exon 7. This alteration has been reported in both the homozygous and heterozygous state in multiple patients with Bloom syndrome (German J et al. Hum. Mutat. 2007 Aug;28:743-53; Renes JS et al. J. Clin. Endocrinol. Metab. 2013 Oct;98:3932-8; Schoenaker MHD et al. J. Clin. Immunol., 2018 01;38:35-44). This alteration was also identified in multiple relatives with early onset breast cancer from one family (Thompson ER et al. PLoS Genet. 2012 Sep;8:e1002894). Additionally, this alteration was identified in a patient with Ewing sarcoma and in multiple patients with colorectal cancer (Dobbins SE et al. Fam. Cancer, 2016 10;15:593-9; Brohl AS et al. Genet. Med., 2017 08;19:955-958; AlDubayan SH et al. Am. J. Hum. Genet., 2018 03;102:401-414). 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

A;A

Vest4

0.94

GERP RS

4.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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