NM_000057.4(BLM):c.2851_2857del (p.Met951fs) AND Bloom syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: May 18, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000694716.8

Allele description [Variation Report for NM_000057.4(BLM):c.2851_2857del (p.Met951fs)]

NM_000057.4(BLM):c.2851_2857del (p.Met951fs)

Gene:

BLM:BLM RecQ like helicase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

15q26.1

Genomic location:

Preferred name:

NM_000057.4(BLM):c.2851_2857del (p.Met951fs)

HGVS:

NC_000015.10:g.90790676_90790682del
NG_007272.1:g.78305_78311del
NM_000057.4:c.2851_2857delMANE SELECT
NM_001287246.2:c.2851_2857del
NM_001287247.2:c.2851_2857del
NM_001287248.2:c.1726_1732del
NP_000048.1:p.Met951fs
NP_001274175.1:p.Met951fs
NP_001274176.1:p.Met951fs
NP_001274177.1:p.Met576fs
LRG_20:g.78305_78311del
NC_000015.9:g.91333903_91333909del
NC_000015.9:g.91333906_91333912del
NM_000057.2:c.2851_2857delATGGGGA
NM_000057.3:c.2851_2857del
NM_000057.3:c.2851_2857delATGGGGA

Protein change:

M576fs

Links:

dbSNP: rs1309932713

NCBI 1000 Genomes Browser:

rs1309932713

Molecular consequence:

NM_000057.4:c.2851_2857del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001287246.2:c.2851_2857del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001287247.2:c.2851_2857del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001287248.2:c.1726_1732del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Bloom syndrome (BLM)
Synonyms:: Bloom-Torre-Machacek syndrome; Growth deficiency, sun-sensitive, telangiectatic, hypo and hyperpigmented skin, predisposition to malignancy and chromosomal instability
Identifiers:: MONDO: MONDO:0008876; MedGen: C0005859; Orphanet: 125; OMIM: 210900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000823173	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17407155, 28492532
SCV002011811	GeneID Lab - Advanced Molecular Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 5, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17407155, 25741868
SCV004210891	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 18, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000823173

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 24, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002011811

GeneID Lab - Advanced Molecular Diagnostics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 5, 2019)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004210891

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 18, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
African American	germline	no	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry.

German J, Sanz MM, Ciocci S, Ye TZ, Ellis NA.

Hum Mutat. 2007 Aug;28(8):743-53.

PubMed [citation]

PMID:: 17407155

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000823173.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 573132). This variant has not been reported in the literature in individuals affected with BLM-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Met951Leufs*9) 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneID Lab - Advanced Molecular Diagnostics, SCV002011811.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	African American	1	not provided	not provided	clinical testing	PubMed (2)

Description

This variant creates a premature translational stop signal described as p.Met951LeufsTer9 in the BLM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BLM have been previously described as pathogenic (PMID: 17407155). To the best of our knowledge, this variant has not been described in medical literature and it is not present on the gnomAD exomes database. Based on these findings and the limited literature regarding this substitution we consider it a “likely pathogenic variant”.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV004210891.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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