NM_007294.3(BRCA1):c.5468-2A>G AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Pathogenic (Last evaluated: Sep 11, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000637422.3

Allele description [Variation Report for NM_007294.3(BRCA1):c.5468-2A>G]

NM_007294.3(BRCA1):c.5468-2A>G

Gene:
BRCA1:BRCA1 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q21.31
Genomic location:
Preferred name:
NM_007294.3(BRCA1):c.5468-2A>G
HGVS:
  • NC_000017.11:g.43045804T>C
  • NG_005905.2:g.172180A>G
  • NM_007294.3:c.5468-2A>G
  • NM_007297.4:c.5327-2A>G
  • NM_007298.3:c.2156-2A>G
  • NM_007299.4:c.2082-2A>G
  • NM_007300.4:c.5531-2A>G
  • LRG_292t1:c.5468-2A>G
  • LRG_292:g.172180A>G
  • NC_000017.10:g.41197821T>C
  • NM_007294.4:c.5468-2A>GMANE SELECT
Nucleotide change:
IVS23-2A>G
Links:
dbSNP: rs398122699
NCBI 1000 Genomes Browser:
rs398122699
Molecular consequence:
  • NM_007294.3:c.5468-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007297.4:c.5327-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007298.3:c.2156-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007299.4:c.2082-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007300.4:c.5531-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
Functional consequence:
functionally_abnormal [Sequence Ontology: SO:0002218] - Comment(s)

Condition(s)

Name:
Hereditary breast and ovarian cancer syndrome (HBOC)
Synonyms:
Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC)
Identifiers:
MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145; OMIM: PS604370

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000758879Invitaecriteria provided, single submitter
Pathogenic
(Sep 11, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations.

Golmard L, Delnatte C, Laugé A, Moncoutier V, Lefol C, Abidallah K, Tenreiro H, Copigny F, Giraudeau M, Guy C, Barbaroux C, Amorim G, Briaux A, Guibert V, Tarabeux J, Caputo S, Collet A, Gesta P, Ingster O, Stern MH, Rouleau E, de Pauw A, et al.

Oncogene. 2016 Mar 10;35(10):1324-7. doi: 10.1038/onc.2015.181. Epub 2015 Jun 1.

PubMed [citation]
PMID:
26028024

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
PMID:
17576681
PMCID:
PMC1934990
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000758879.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change affects an acceptor splice site in the last intron (intron 22) of the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with early-onset ovarian cancer (PMID: 26028024). ClinVar contains an entry for this variant (Variation ID: 91653). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and/or protein function (PMID: 30209399). 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: Sep 18, 2021

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