NM_000057.4(BLM):c.2187del (p.Leu730fs) AND Bloom syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 26, 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:: RCV002510388.3

Allele description [Variation Report for NM_000057.4(BLM):c.2187del (p.Leu730fs)]

NM_000057.4(BLM):c.2187del (p.Leu730fs)

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.2187del (p.Leu730fs)

HGVS:

NC_000015.10:g.90765408del
NG_007272.1:g.53037del
NM_000057.4:c.2187delMANE SELECT
NM_001287246.2:c.2187del
NM_001287247.2:c.2187del
NM_001287248.2:c.1062del
NP_000048.1:p.Leu730Trpfs
NP_000048.1:p.Leu730fs
NP_001274175.1:p.Leu730fs
NP_001274176.1:p.Leu730fs
NP_001274177.1:p.Leu355fs
LRG_20t1:c.2187del
LRG_20:g.53037del
LRG_20p1:p.Leu730Trpfs
NC_000015.9:g.91308637del
NC_000015.9:g.91308638del
NM_000057.2:c.2187delC
NM_000057.3:c.2187delC

Protein change:

L355fs

Molecular consequence:

NM_000057.4:c.2187del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001287246.2:c.2187del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001287247.2:c.2187del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001287248.2:c.1062del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV002819645	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Dec 19, 2022)	germline	clinical testing	Citation Link,
SCV004655555	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17407155, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002819645

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Dec 19, 2022)

germline

clinical testing

Citation Link,

SCV004655555

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 26, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002819645.1

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

Description

Variant summary: BLM c.2187delC (p.Leu730TrpfsX8) 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 251280 control chromosomes. To our knowledge, no occurrence of c.2187delC in individuals affected with Bloom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004655555.1

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

Description

This sequence change creates a premature translational stop signal (p.Leu730Trpfs*8) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1878335). This variant has not been reported in the literature in individuals affected with BLM-related conditions. This variant is not present in population databases (gnomAD no frequency).

#	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

Last Updated: Sep 29, 2024

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