NM_000057.4(BLM):c.3956del (p.Ile1319fs) AND Bloom syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 3, 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:: RCV000669899.7

Allele description [Variation Report for NM_000057.4(BLM):c.3956del (p.Ile1319fs)]

NM_000057.4(BLM):c.3956del (p.Ile1319fs)

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.3956del (p.Ile1319fs)

HGVS:

NC_000015.10:g.90811286del
NG_007272.1:g.98915del
NM_000057.4:c.3956delMANE SELECT
NM_001287246.2:c.3956del
NM_001287247.2:c.3563del
NM_001287248.2:c.2831del
NP_000048.1:p.Ile1319fs
NP_001274175.1:p.Ile1319fs
NP_001274176.1:p.Ile1188fs
NP_001274177.1:p.Ile944fs
LRG_20:g.98915del
NC_000015.9:g.91354516del
NM_000057.3:c.3956del
NM_000057.3:c.3956delT

Protein change:

I1188fs

Links:

dbSNP: rs1555425080

NCBI 1000 Genomes Browser:

rs1555425080

Molecular consequence:

NM_000057.4:c.3956del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001287246.2:c.3956del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001287247.2:c.3563del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001287248.2:c.2831del - 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

Recent activity

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high affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A-like isoform X1 [P...
high affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A-like isoform X1 [Phyllopteryx taeniolatus]
gi|2639057359|ref|XP_061635593.1|

Protein
JGI_XZT66693.fwd NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7785692 5'...
JGI_XZT66693.fwd NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7785692 5', mRNA sequence
gi|74304895|gnl|dbEST|31380421|gb|C 70.2|

Nucleotide
BX849864 Wellcome CRC pCS2+ st19-26 Xenopus laevis cDNA clone IMAGp998I029331; I...
BX849864 Wellcome CRC pCS2+ st19-26 Xenopus laevis cDNA clone IMAGp998I029331; IMAGE:4058953 5', mRNA sequence
gi|39738499|gnl|dbEST|20905701|emb| 864.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000794698	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Oct 13, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001219727	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 3, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9388480, 10569803, 27657136, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000794698

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Oct 13, 2017)

unknown

clinical testing

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

Citation Link,

SCV001219727

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 3, 2023)

germline

clinical testing

PubMed (4)
[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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

BLM (the causative gene of Bloom syndrome) protein translocation into the nucleus by a nuclear localization signal.

Kaneko H, Orii KO, Matsui E, Shimozawa N, Fukao T, Matsumoto T, Shimamoto A, Furuichi Y, Hayakawa S, Kasahara K, Kondo N.

Biochem Biophys Res Commun. 1997 Nov 17;240(2):348-53.

PubMed [citation]

PMID:: 9388480

Localization of the Bloom syndrome helicase to punctate nuclear structures and the nuclear matrix and regulation during the cell cycle: comparison with the Werner's syndrome helicase.

Gharibyan V, Youssoufian H.

Mol Carcinog. 1999 Dec;26(4):261-73.

PubMed [citation]

PMID:: 10569803

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000794698.1

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001219727.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the nuclear localization signal (NLS) and the topoisomerase I (TOP1) domain of BLM protein, which are critical for BLM localization to the nucleus and TOP1-mediated RNA:DNA unwinding (PMID: 27657136, 9388480, 10569803, 27657136). While functional studies have not been performed to directly test the effect of this variant on BLM protein function, this suggests that disruption of this region of the protein is causative of disease. ClinVar contains an entry for this variant (Variation ID: 554289). 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). This sequence change creates a premature translational stop signal (p.Ile1319Asnfs*87) in the BLM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acid(s) of the BLM protein.

#	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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