NM_000057.4(BLM):c.98+1G>A AND Bloom syndrome

Clinical significance:Likely pathogenic (Last evaluated: Aug 31, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000409688.3

Allele description [Variation Report for NM_000057.4(BLM):c.98+1G>A]

NM_000057.4(BLM):c.98+1G>A

Gene:
BLM:BLM RecQ like helicase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q26.1
Genomic location:
Preferred name:
NM_000057.4(BLM):c.98+1G>A
HGVS:
  • NC_000015.10:g.90747491G>A
  • NG_007272.1:g.35120G>A
  • NM_000057.4:c.98+1G>AMANE SELECT
  • NM_001287246.2:c.98+1G>A
  • NM_001287247.2:c.98+1G>A
  • NM_001287248.2:c.-1194+1G>A
  • LRG_20:g.35120G>A
  • NC_000015.9:g.91290721G>A
  • NM_000057.3:c.98+1G>A
Links:
Counsyl: 281137; dbSNP: rs750293380
NCBI 1000 Genomes Browser:
rs750293380
Molecular consequence:
  • NM_000057.4:c.98+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001287246.2:c.98+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001287247.2:c.98+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001287248.2:c.-1194+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000486519Counsylcriteria provided, single submitter
Likely pathogenic
(Jun 15, 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,

SCV001390676Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 31, 2020)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933
See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000486519.1

#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, SCV001390676.2

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

Description

This sequence change affects a donor splice site in intron 2 of the BLM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs750293380, ExAC 0.008%). Disruption of this splice site has been observed in combination with another BLM variant in an individual with clinical features of Bloom syndrome (PMID: 17407155), and it has also been observed in the heterozygous state in individuals affected with colorectal cancer (PMID: 26358404). ClinVar contains an entry for this variant (Variation ID: 371055). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). 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.

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

Last Updated: Oct 7, 2021

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