NM_007294.3(BRCA1):c.4986+5G>A AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jan 30, 2019)

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:
RCV000197490.4

Allele description [Variation Report for NM_007294.3(BRCA1):c.4986+5G>A]

NM_007294.3(BRCA1):c.4986+5G>A

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.4986+5G>A
HGVS:
  • NC_000017.11:g.43070923C>T
  • NG_005905.2:g.147061G>A
  • NM_007294.3:c.4986+5G>A
  • NM_007297.4:c.4845+5G>A
  • NM_007298.3:c.1674+5G>A
  • NM_007299.4:c.1674+5G>A
  • NM_007300.4:c.5049+5G>A
  • LRG_292t1:c.4986+5G>A
  • LRG_292:g.147061G>A
  • NC_000017.10:g.41222940C>T
  • NM_007294.4:c.4986+5G>AMANE SELECT
  • U14680.1:n.5105+5G>A
Nucleotide change:
IVS16+5G>A
Links:
Breast Cancer Information Core (BIC) (BRCA1): 5105+5&base_change=G to A; dbSNP: rs397509211
NCBI 1000 Genomes Browser:
rs397509211
Molecular consequence:
  • NM_007294.3:c.4986+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007297.4:c.4845+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007298.3:c.1674+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007299.4:c.1674+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007300.4:c.5049+5G>A - intron variant - [Sequence Ontology: SO:0001627]
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
SCV000253714Invitaecriteria provided, single submitter
Pathogenic
(Jan 30, 2019)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000918764Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Dec 21, 2017)
germlineclinical testing

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

Citation Link

Summary from all submissions

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

Citations

PubMed

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

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]
PMID:
9536098
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000253714.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change falls in intron 15 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with breast cancer (PMID: 23239986). ClinVar contains an entry for this variant (Variation ID: 96936). 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: 23239986, 23451180, 30209399). For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918764.1

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

Description

Variant summary: The BRCA1 c.4986+5G>A variant (alternatively known as IVS16+5G>A and 5105+5G>A) involves the alteration of a conserved intronic nucleotide and is predicted to impact splicing by 4/5 splice prediction tools. Mutation taster also predicts a damaging outcome for this variant. This variant is absent in 244498 control chromosomes (gnomAD). This variant has been reported in breast and pancreatic cancer patients in the literature (Wappenschmidt_2012, Mandelker_2017) and functional studies show that it leads to the retention of 65 nucleotides of the 5' end of intron 15 which leads to premature truncation of the BRCA1 protein (p.Met1663Valfs*14) (Wappenschmidt_2012, Colombo_2013). Other similar variants (c.4986+3G>C, c.4986+4A>G, c.4986+5G>T and c.4986+6T>C) were found to cause the incorporation of the 65 intronic nucleotides [Wappenschmidt_2012, Vreeswijk_2009 (PMID: 18693280)]. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as likely pathogenic.

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

Last Updated: Sep 18, 2021

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