VCV000005454.44 - ClinVar

NM_000057.4(BLM):c.2207_2212delinsTAGATTC (p.Tyr736fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(19)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000057.4(BLM):c.2207_2212delinsTAGATTC (p.Tyr736fs)

Variation ID: 5454 Accession: VCV000005454.44

Type and length

Indel, 7 bp

Location

Cytogenetic: 15q26.1 15: 90766923-90766928 (GRCh38) [ NCBI UCSC ] 15: 91310153-91310158 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 3, 2013	Oct 20, 2024	Mar 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000057.4:c.2207_2212delinsTAGATTC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000048.1:p.Tyr736fs	frameshift
NM_000057.2:c.2207_2212del6ins7
NM_000057.3:c.2207_2212delATCTGAinsTAGATTC
NM_001287246.2:c.2207_2212delinsTAGATTC	NP_001274175.1:p.Tyr736fs	frameshift
NM_001287247.2:c.2207_2212delinsTAGATTC	NP_001274176.1:p.Tyr736fs	frameshift
NM_001287248.2:c.1082_1087delinsTAGATTC	NP_001274177.1:p.Tyr361fs	frameshift
NC_000015.10:g.90766923_90766928delinsTAGATTC
NC_000015.9:g.91310153_91310158delinsTAGATTC
NG_007272.1:g.54552_54557delATCTGAinsTAGATTC
NG_007272.1:g.54552_54557delinsTAGATTC
LRG_20:g.54552_54557delinsTAGATTC

... more HGVS ... less HGVS

Protein change

Y736fs, Y361fs

Other names

2281del6ins7
Y735fs
BLM, 6-BP DEL/7-BP INS
blmAsh allele
p.Tyr736Leufs*5

Canonical SPDI

NC_000015.10:90766922:ATCTGA:TAGATTC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA284839 Genetic Testing Registry (GTR): GTR000321624 Genetic Testing Registry (GTR): GTR000325413 OMIM: 604610.0001 dbSNP: rs113993962 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BLM		-	-	GRCh38 GRCh37	4377	4429

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Bloom syndrome	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Mar 27, 2024	RCV000005787.37
not provided	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jan 16, 2023	RCV000058933.30
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, single submitter	Apr 14, 2022	RCV000562115.15
BLM-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 19, 2024	RCV004745147.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 06, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000700669.2 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (1) PubMed: 7585968 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BLM Number of individuals with the variant: 11 Sex: mixed
Pathogenic (Oct 18, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194205.1 First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020	Publications: PubMed (4) PubMed: 17407155‚ 7585968‚ 9837821‚ 10090915 Comment: NM_000057.2(BLM):c.2207_2212del6ins7(Y736Lfs5) is classified as pathogenic in the context of Bloom syndrome. Sources cited for classification include the following: PMID: 17407155, 7585968, 9837821, and 10090915. Classification … (more) NM_000057.2(BLM):c.2207_2212del6ins7(Y736Lfs5) 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. (less)
Pathogenic (Oct 14, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000694477.2 First in ClinVar: Apr 16, 2017 Last updated: Jun 22, 2020	Publications: PubMed (2) PubMed: 17407155‚ 26788541 Comment: 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 … (more) 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. (less)
Likely pathogenic (Jun 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501598.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000838965.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Pathogenic (Mar 21, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bloom syndrome (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Study: CSER-MedSeq Accession: SCV000245583.2 First in ClinVar: Sep 14, 2015 Last updated: Apr 20, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (Oct 19, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915701.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (5) PubMed: 7585968‚ 9837821‚ 10521302‚ 20301572‚ 17407155 Comment: 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', … (more) 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. (less)
Pathogenic (Sep 16, 2021)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV002012397.2 First in ClinVar: Nov 13, 2021 Last updated: Dec 24, 2022	Comment: 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 … (more) 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. (less)
Pathogenic (Apr 21, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149199.8 First in ClinVar: May 14, 2014 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Jan 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226754.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (4) PubMed: 10521302‚ 17407155‚ 26788541‚ 9837821 Comment: PP4, PM2, PM3, PS3_moderate, PS4_moderate, PVS1 Number of individuals with the variant: 1
Pathogenic (Apr 14, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000672932.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (7) PubMed: 12702560‚ 15726604‚ 21815139‚ 23225144‚ 24096176‚ 29056561‚ 29506128 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004210835.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Mar 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV003917426.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: BLM: PVS1, PM2, PP4 Number of individuals with the variant: 2
Pathogenic (Sep 20, 2002)	no assertion criteria provided Method: literature only	BLOOM SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025969.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015	Publications: PubMed (5) PubMed: 7585968‚ 9482582‚ 9837821‚ 10090915‚ 12242432 Comment on evidence: In 4 ostensibly unrelated persons of Jewish ancestry with Bloom syndrome (BLM; 210900), Ellis et al. (1995) found homozygosity for a 6-bp deletion/7-bp insertion at … (more) In 4 ostensibly unrelated persons of Jewish ancestry with Bloom syndrome (BLM; 210900), Ellis et al. (1995) found homozygosity for a 6-bp deletion/7-bp insertion at nucleotide 2281 of the BLM cDNA. Deletion of ATCTGA and insertion of TAGATTC caused the insertion of the novel codons for LDSR after amino acid 736, and after these codons there was a stop codon. Ellis et al. (1995) concluded that a person carrying this deletion/insertion mutation was a founder of the Ashkenazi-Jewish population, and that nearly all Ashkenazi Jews with Bloom syndrome inherited the mutation identical by descent from this common ancestor. Identification of the mutation by a PCR test was now possible for screening for carriers among Ashkenazim. Straughen et al. (1998) described a rapid method for detecting the 6-bp deletion/7-bp insertion, a predominant Ashkenazi Jewish mutation in Bloom syndrome. They commented that in the Bloom syndrome registry, one or both parents of 52 of the 168 registered persons are Ashkenazi Jews. Using a convenient PCR assay, Ellis et al. (1998) found the 6-bp del/7-bp ins mutation, blm(Ash), on 58 of 60 chromosomes transmitted by Ashkenazi parents to persons with Bloom syndrome. In contrast, in 91 unrelated non-Ashkenazic persons with BS whom they examined, blm(Ash) was identified in only 5, these coming from Spanish-speaking Christian families from the southwestern United States, Mexico, or El Salvador. These data, along with haplotype analyses, showed that blm(Ash) was independently established through a founder effect in Ashkenazi Jews and in immigrants to formerly Spanish colonies. This striking observation underscored the complexity of Jewish history and demonstrated the importance of migration and genetic drift in the formation of human populations. In a study of the frequency of the BLM 6-bp del/7-bp ins mutation in a group of Ashkenazi Jews, unselected for personal or family history of Bloom syndrome, Oddoux et al. (1999) found the mutation in 5 of 1,155 individuals, yielding a frequency of 1/231 (95% CI, 1/123-1/1,848). The low frequency is consistent with an absence of heterozygote advantage for carriers of 1 copy of the mutant allele. The frequency of heterozygotes for other autosomal recessive conditions within their panel had been validated in other studies, suggesting that the test panel was representative of the Ashkenazi Jewish population. Those frequencies were Tay-Sachs disease, 1/28; cystic fibrosis, 1/25; Gaucher disease, 1/15; BRCA2, 6174delT, 1/106; Canavan disease, 1/41; and Fanconi anemia complementation group C, 1/116. To determine whether carriers of BLM mutations are at increased risk of colorectal cancer, Gruber et al. (2002) genotyped 1,244 cases of colorectal cancer and 1,839 controls, both of Ashkenazi Jewish ancestry, to estimate the relative risk of colorectal cancer among carriers of the BLM(Ash) founder mutation. Ashkenazi Jews with colorectal cancer were more than twice as likely to carry the BLM(Ash) mutation than Ashkenazi Jewish controls without colorectal cancer (odds ratio = 2.45, 95% CI 1.3 to 4.8; P = 0.0065). Gruber et al. (2002) verified that the APC I1307K mutation (611731.0029) did not confound their results. (less)
Pathogenic (Jul 19, 2024)	no assertion criteria provided Method: clinical testing	BLM-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005361674.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The BLM c.2207_2212delinsTAGATTC variant is predicted to result in a frameshift and premature protein termination (p.Tyr736Leufs5). The BLM c.2207_2212delATCTGAinsTAGATTC (p.Tyr736LeufsTer5) variant is well described in … (more) The BLM c.2207_2212delinsTAGATTC variant is predicted to result in a frameshift and premature protein termination (p.Tyr736Leufs5). 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 (GeneReviews, https://www.ncbi.nlm.nih.gov/books/NBK1398/). This variant has been reported in numerous individuals of AJ descent in the homozygous and compound heterozygous states (Ellis et al. 1995. PubMed ID: 7585968; Ellis et al. 1998. PubMed ID: 9837821; German et al. 2007. PubMed ID: 17407155). This variant has also been reported in the homozygous and compound heterozygous states in individuals of Spanish American ancestry (German et al. 2007. PubMed ID: 17407155). Functional studies utilizing cells derived from a skin biopsy obtained from an individual homozygous for the c.2207_2212delATCTGAinsTAGATTC (p.Tyr736LeufsTer5) variant showed the variant did not create BLM protein (Ellis et al. 1999. PubMed ID: 10521302). This variant has not been reported in a large population database, indicating it is rare. This variant is reported as pathogenic and likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/5454/). Frameshift variants in BLM are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. (less)
Pathogenic (Jul 24, 2014)	no assertion criteria provided Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000189875.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014	Publications: PubMed (4) PubMed: 17407155‚ 9837821‚ 20301572‚ 23225144
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: germline	SNPedia Accession: SCV000090454.1 First in ClinVar: Oct 22, 2013 Last updated: Oct 22, 2013
not provided (-)	no classification provided Method: literature only	Bloom syndrome Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000058501.3 First in ClinVar: May 03, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 20301572‚ 9837821 BookShelf: NBK1398 BookShelf: NBK1398
Uncertain significance (Oct 05, 2021)	Flagged submission flagged submission (Sema4 Curation Guidelines) Method: curation Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529259.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The BLM c.2207_2212delATCTGAinsTAGATTC (p.Y736LfsX5) variant has been reported in several individuals with Bloom syndrome (PMID: 7585968, 9837821). This variant is a well-established pathogenic variant associated … (more) The BLM c.2207_2212delATCTGAinsTAGATTC (p.Y736LfsX5) variant has been reported in several individuals with Bloom syndrome (PMID: 7585968, 9837821). This variant is a well-established pathogenic variant associated with Bloom syndrome (PMID: 9837821). This variant causes a frameshift at amino acid 736 that results in premature termination 5 amino acids downstream. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant was not observed in the Genome Aggregation Database (http://gnomad.broadinstitute.org). The variant has been reported in ClinVar (Variation ID: 5454). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (2) PubMed: 7585968‚ 9837821
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Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

The BLM c.2207_2212delinsTAGATTC variant is predicted to result in a frameshift and premature protein termination (p.Tyr736Leufs*5). 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 (GeneReviews, https://www.ncbi.nlm.nih.gov/books/NBK1398/). This variant has been reported in numerous individuals of AJ descent in the homozygous and compound heterozygous states (Ellis et al. 1995. PubMed ID: 7585968; Ellis et al. 1998. PubMed ID: 9837821; German et al. 2007. PubMed ID: 17407155). This variant has also been reported in the homozygous and compound heterozygous states in individuals of Spanish American ancestry (German et al. 2007. PubMed ID: 17407155). Functional studies utilizing cells derived from a skin biopsy obtained from an individual homozygous for the c.2207_2212delATCTGAinsTAGATTC (p.Tyr736LeufsTer5) variant showed the variant did not create BLM protein (Ellis et al. 1999. PubMed ID: 10521302). This variant has not been reported in a large population database, indicating it is rare. This variant is reported as pathogenic and likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/5454/). Frameshift variants in BLM are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Bloom Syndrome.	Adam MP	-	2023	PMID: 20301572
Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms.	Lowery MA	Journal of the National Cancer Institute	2018	PMID: 29506128
Bloom syndrome does not always present with sun-sensitive facial erythema.	Bouman A	European journal of medical genetics	2018	PMID: 29056561
Cellular defects caused by hypomorphic variants of the Bloom syndrome helicase gene BLM.	Shastri VM	Molecular genetics & genomic medicine	2015	PMID: 26788541
A common nonsense mutation of the BLM gene and prostate cancer risk and survival.	Antczak A	Gene	2013	PMID: 24096176
Nonsense mutation p.Q548X in BLM, the gene mutated in Bloom's syndrome, is associated with breast cancer in Slavic populations.	Prokofyeva D	Breast cancer research and treatment	2013	PMID: 23225144
High prevalence and breast cancer predisposing role of the BLM c.1642 C>T (Q548X) mutation in Russia.	Sokolenko AP	International journal of cancer	2012	PMID: 21815139
Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry.	German J	Human mutation	2007	PMID: 17407155
Coinheritance of BRCA1 and BRCA2 mutations with Fanconi anemia and Bloom syndrome mutations in Ashkenazi Jewish population: possible role in risk modification for cancer development.	Koren-Michowitz M	American journal of hematology	2005	PMID: 15726604
Heterozygosity for the BLM(Ash) mutation and cancer risk.	Cleary SP	Cancer research	2003	PMID: 12702560
BLM heterozygosity and the risk of colorectal cancer.	Gruber SB	Science (New York, N.Y.)	2002	PMID: 12242432
Transfection of BLM into cultured bloom syndrome cells reduces the sister-chromatid exchange rate toward normal.	Ellis NA	American journal of human genetics	1999	PMID: 10521302
Prevalence of Bloom syndrome heterozygotes among Ashkenazi Jews.	Oddoux C	American journal of human genetics	1999	PMID: 10090915
The Ashkenazic Jewish Bloom syndrome mutation blmAsh is present in non-Jewish Americans of Spanish ancestry.	Ellis NA	American journal of human genetics	1998	PMID: 9837821
A rapid method for detecting the predominant Ashkenazi Jewish mutation in the Bloom's syndrome gene.	Straughen JE	Human mutation	1998	PMID: 9482582
The Bloom's syndrome gene product is homologous to RecQ helicases.	Ellis NA	Cell	1995	PMID: 7585968
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BLM	-	-	-	-
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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000057.4(BLM):c.2207_2212delinsTAGATTC (p.Tyr736fs)

Variant Details

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Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs113993962 ...