NM_000057.4(BLM):c.1968dup (p.Lys657fs) AND Bloom syndrome

Clinical significance:Pathogenic (Last evaluated: Jul 7, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000586500.6

Allele description [Variation Report for NM_000057.4(BLM):c.1968dup (p.Lys657fs)]

NM_000057.4(BLM):c.1968dup (p.Lys657fs)

Gene:
BLM:BLM RecQ like helicase [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
15q26.1
Genomic location:
Preferred name:
NM_000057.4(BLM):c.1968dup (p.Lys657fs)
HGVS:
  • NC_000015.10:g.90763051dup
  • NG_007272.1:g.50680dup
  • NM_000057.4:c.1968dupMANE SELECT
  • NM_001287246.2:c.1968dup
  • NM_001287247.2:c.1968dup
  • NM_001287248.2:c.843dup
  • NP_000048.1:p.Lys657fs
  • NP_001274175.1:p.Lys657fs
  • NP_001274176.1:p.Lys657fs
  • NP_001274177.1:p.Lys282fs
  • LRG_20t1:c.1968dup
  • LRG_20:g.50680dup
  • NC_000015.9:g.91306280_91306281insG
  • NC_000015.9:g.91306281dup
  • NM_000057.2:c.1968dup
  • NM_000057.2:c.1968dupG
  • NM_000057.3:c.1968dup
Protein change:
K282fs
Links:
dbSNP: rs772785079
NCBI 1000 Genomes Browser:
rs772785079
Molecular consequence:
  • NM_000057.4:c.1968dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001287246.2:c.1968dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001287247.2:c.1968dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001287248.2:c.843dup - 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; 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
SCV000694475Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Dec 1, 2019)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001132141Counsylno assertion criteria providedLikely pathogenic
(Mar 16, 2015)
unknownclinical testing

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

SCV001209121Invitaecriteria provided, single submitter
Pathogenic
(Jul 7, 2020)
germlineclinical testing

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

SCV002025227PerkinElmer Genomicsno assertion criteria providedPathogenic
(Feb 20, 2019)
germlineclinical testing

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

A novel frameshift mutation in BLM gene associated with high sister chromatid exchanges (SCE) in heterozygous family members.

Ben Salah G, Hadj Salem I, Masmoudi A, Kallabi F, Turki H, Fakhfakh F, Ayadi H, Kamoun H.

Mol Biol Rep. 2014 Nov;41(11):7373-80. doi: 10.1007/s11033-014-3624-5. Epub 2014 Aug 17.

PubMed [citation]
PMID:
25129257
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694475.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: BLM c.1968dupG (p.Lys657GlufsX5) 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 allele was found at a frequency of 1.2e-05 in 251206 control chromosomes. c.1968dupG has been reported in the literature in at-least one homozygous individual born to consanguineous parents, affected with Bloom Syndrome and included in the Bloom syndrome registry (German_2007). It has subsequently been cited as a pathogenic variant in reports of carrier screening for BLM syndrome (Perreault-Micale_2015) and other literature (de Voer_2015, Salah_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The variant has been observed at-least twice among individuals undergoing carrier screening at our laboratory. No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was re-classified as pathogenic.

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

From Counsyl, SCV001132141.1

#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 Invitae, SCV001209121.2

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

Description

This sequence change creates a premature translational stop signal (p.Lys657Glufs*5) in the BLM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs772785079, ExAC 0.001%). This variant has been observed in an individual affected with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 495425). 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

From PerkinElmer Genomics, SCV002025227.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 28, 2021

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