rs113993962

chr15-90766922-TATCTGA-TTAGATTC

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_000057.4(BLM):c.2207_2212delinsTAGATTC(p.Tyr736LeufsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BLM NM_000057.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15 U:1 O:2
• Conservation: PhyloP100: 7.36

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-90766923-ATCTGA-TAGATTC is Pathogenic according to our data. Variant chr15-90766923-ATCTGA-TAGATTC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5454.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=12, Uncertain_significance=1, Likely_pathogenic=1, not_provided=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4	c.2207_2212delinsTAGATTC	p.Tyr736LeufsTer5	frameshift_variant	10/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8	c.2207_2212delinsTAGATTC	p.Tyr736LeufsTer5	frameshift_variant	10/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:15 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bloom syndrome Pathogenic:9 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_000057.2(BLM):c.2207_2212del6ins7(Y736Lfs*5) is classified as pathogenic in the context of Bloom syndrome. Sources cited for classification include the following: PMID: 17407155, 7585968, 9837821, and 10090915. Classification of NM_000057.2(BLM):c.2207_2212del6ins7(Y736Lfs*5) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 20, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 25, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2019	The p.Tyr736LeufsX5 variant in BLM was first reported in 4 Ashkenazi Jewish individuals with Bloom syndrome in the homozygous state (Ellis 1995), and is the most common pathogenic variant in Ashkenazi Jewish individuals in whom it occurs in ~1/111 individuals (Pagan 2002). In vitro functional studies also provide some evidence that the p.Tyr736LeufsX5 variant may impact protein function (Ellis 1995). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 736 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Bloom syndrome in an autosomal recessive manner. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 14, 2019	Variant summary: BLM c.2207_2212delinsTAGATTC (p.Tyr736LeufsX5) 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 was absent in 249632 control chromosomes (gnomAD). c.2207_2212delinsTAGATTC has been reported in the literature in multiple individuals (both compound heterozygous and homozygous) affected with Bloom Syndrome in Ashkenazi Jewish or Spanish American ancestry (German_2007). This variant (aka blmAsh in the literature), is a well described pathogenic founder mutation in Ashkenazi Jewish population. At least one publication reports experimental evidence evaluating an impact on protein function. Skin fibroblast cell lines established from a person who was homozygous for this variant (GM08505) exhibit a spontaneous, approximately 10-fold increase in the frequency of SCEs (sister chromatid exchanges) compared to cells from unaffected persons. They also present with quadriradial chromosomes in metaphase spreads, are hypersensitive to genotoxic agent hydroxyurea, and show a delay in activating the DNA damage response after exposure to the topoisomerase poison CPT (Shastri_2015). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 19, 2018	The BLM c.2207_2212delATCTGAinsTAGATTC (p.Tyr736LeufsTer5) variant is well described in the literature as a founder mutation in the Ashkenazi Jewish (AJ) population, commonly known as 'blmAsh', and accounts for 97% of all pathogenic variants reported in the AJ population (Sanz et al. 2016). The p.Tyr736LeufsTer5 variant results in a frameshift and is predicted to result in premature termination of the protein. Among probands of full or half AJ descent, the p.Tyr736LeufsTer5 variant has been reported in at least 27 individuals in a homozygous state and eight individuals in a compound heterozygous state (Ellis et al. 1995; Ellis et al. 1998; German et al. 2007). Among probands of Spanish American ancestry, the p.Tyr736LeufsTer5 variant has been reported in at least three individuals in a homozygous state, and two individuals in a compound heterozygous state (German et al. 2007). The p.Tyr736LeufsTer5 variant has also been detected in at least 52 parents who were unaffected carriers (Ellis et al. 1998). Control data are unavailable for this variant, and the p.Tyr736LeufsTer5 variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium, in a region with good sequence coverage, and hence is presumed to be rare in the general population. Ellis et al. (1999) report that a SV40-transformed fibroblast cell line, derived from a skin biopsy sample obtained from an individual homozygous for the p.Tyr736LeufsTer5 variant was effectively null for the BLM protein. Based on the collective evidence, the p.Tyr736LeufsTer5 variant is classified as pathogenic for Bloom syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 16, 2021	The BLM c.2207_2212delinsTAGATTC (p.Tyr736LeufsTer5) change results from the deletion of 6 nucleotides and insertion of 7 nucleotides to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense-mediated decay (PVS1). This variant has a maximum subpopulation frequency of 0.38% in gnomAD v2.1.1, where it is primarily found in the Ashkenazi Jewish population (https://gnomad.broadinstitute.org/variant/15-91310152-TATC-T). This variant has been reported in the homozygous and compound heterozygous state in many individuals with Bloom syndrome (PS4, PM3; PMID: 7585968, 9837821, 17407155). It is a well-established pathogenic founder variant in Bloom syndrome which is estimated to be found in 1 of 107 individuals in the Ashkenazi Jewish population (PMID: 9758720). Studies of heterozygous carriers of this variant and colorectal cancer risk have been inconclusive. Gruber et al. found that Ashkenazi Jewish individuals with colorectal cancer harbor this alteration twice as frequently as compared to controls (PMID: 12242432), however Clearly et al. were unable to replicate these findings (PMID: 12702560) and Baris et al. did not find an increased risk for colorectal cancer in heterozygous carriers of this variant (PMID: 18210922). As of May 2021, the National Comprehensive Cancer Network (NCCN) suggests that heterozygous carriers of pathogenic variants in BLM may have an increased risk of colorectal cancer, however the exact risk is not well-established. This alteration is also known as ‘blmAsh’ in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM3. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 16, 2023	PP4, PM2, PM3, PS3_moderate, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	BLM: PVS1, PM2, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18264947, 26788541, 21815139, 24096176, 26277320, 29056561, 29506128, 31816118, 34308366, 34994613, 33219493, 35099000, 7585968) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 06, 2017	- -
not provided, no classification provided	literature only	SNPedia	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 14, 2022	The c.2207_2212delATCTGAinsTAGATTC pathogenic mutation, located in coding exon 9 of the BLM gene, results from the deletion of 6 nucleotides and insertion of 7 nucleotides at positions 2207 to 2212, causing a translational frameshift with a predicted alternate stop codon (p.Y736Lfs*5). This is a well-established founder mutation in the Ashkenazi Jewish population, reported in individuals with Bloom syndrome in the homozygous or compound heterozygous state, and is referred to as BLMAsh in the literature (Ellis NA et al. Cell. 1995 Nov;83:655-66; Ellis NA et al. Am. J. Hum. Genet. 1998 Dec;63:1685-93; Oddoux C et al. Am. J. Hum. Genet. 1999 Apr;64:1241-3; Bouman A et al. Eur J Med Genet. 2018 Feb;61:94-97). One study found that this alteration was twice as prevalent in Ashkenazi Jewish individuals with colorectal cancer compared to controls (OR=2.45; 95% CI: 1.3-4.8; p=0.0065); however, another study found no significant difference in the carrier frequency of this mutation in individuals with colorectal cancer compared to individuals with other cancers and unaffected controls in an Ashkenazi Jewish population, and when they combined their data with the previous study, they estimated a more modest association with colorectal cancer (OR=1.79; 95% CI 1.17-2.74; p=0.009) (Gruber SB et al. Science. 2002 Sep;297:2013; Cleary SP et al. Cancer Res. 2003 Apr;63:1769-71). 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113993962; hg19: chr15-91310153;