NM_000057.4(BLM):c.3475_3476del (p.Leu1159fs) AND Bloom syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jul 19, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000034910.6

Allele description [Variation Report for NM_000057.4(BLM):c.3475_3476del (p.Leu1159fs)]

NM_000057.4(BLM):c.3475_3476del (p.Leu1159fs)

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.3475_3476del (p.Leu1159fs)
HGVS:
  • NC_000015.10:g.90803637_90803638del
  • NG_007272.1:g.91266_91267del
  • NM_000057.4:c.3475_3476delMANE SELECT
  • NM_001287246.2:c.3475_3476del
  • NM_001287247.2:c.3358+5300_3358+5301del
  • NM_001287248.2:c.2350_2351del
  • NP_000048.1:p.Leu1159fs
  • NP_001274175.1:p.Leu1159fs
  • NP_001274177.1:p.Leu784fs
  • LRG_20t1:c.3475_3476del
  • LRG_20:g.91266_91267del
  • NC_000015.9:g.91346867_91346868del
  • NM_000057.2:c.3475_3476delTT
  • NM_000057.3:c.3475_3476del
Protein change:
L1159fs
Links:
dbSNP: rs367543033
NCBI 1000 Genomes Browser:
rs367543033
Molecular consequence:
  • NM_000057.4:c.3475_3476del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001287246.2:c.3475_3476del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001287248.2:c.2350_2351del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001287247.2:c.3358+5300_3358+5301del - intron variant - [Sequence Ontology: SO:0001627]

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; MICROCEPHALY, GROWTH RESTRICTION, AND INCREASED SISTER CHROMATID EXCHANGE 1
Identifiers:
MONDO: MONDO:0008876; MedGen: C0005859; Orphanet: 125; OMIM: 210900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000486723Counsylcriteria provided, single submitter
Likely pathogenic
(Jul 26, 2016)
unknownclinical testing

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

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV000916684Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Aug 13, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001406556Invitaecriteria provided, single submitter
Pathogenic
(Jul 19, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A rigorous approach for selection of optimal variant sets for carrier screening with demonstration of clinical utility.

Perreault-Micale C, Davie J, Breton B, Hallam S, Greger V.

Mol Genet Genomic Med. 2015 Jul;3(4):363-73. doi: 10.1002/mgg3.148. Epub 2015 Apr 23.

PubMed [citation]
PMID:
26247052
PMCID:
PMC4521971

Deleterious Germline BLM Mutations and the Risk for Early-onset Colorectal Cancer.

de Voer RM, Hahn MM, Mensenkamp AR, Hoischen A, Gilissen C, Henkes A, Spruijt L, van Zelst-Stams WA, Kets CM, Verwiel ET, Nagtegaal ID, Schackert HK, van Kessel AG, Hoogerbrugge N, Ligtenberg MJ, Kuiper RP.

Sci Rep. 2015 Sep 11;5:14060. doi: 10.1038/srep14060.

PubMed [citation]
PMID:
26358404
PMCID:
PMC4566092
See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000486723.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916684.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: BLM c.3475_3476delTT (p.Leu1159IlefsX6) 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. The variant allele was found at a frequency of 4.1e-06 in 246224 control chromosomes (gnomAD). The variant, c.3475_3476delTT, has been reported in the literature in individuals affected with Bloom Syndrome (German_2007). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001406556.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Leu1159Ilefs*6) in the BLM gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 42084). Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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