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NM_000059.4(BRCA2):c.8331+2T>C AND Hereditary breast ovarian cancer syndrome

Germline classification:
Pathogenic (4 submissions)
Last evaluated:
Jan 16, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000496246.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.8331+2T>C]

NM_000059.4(BRCA2):c.8331+2T>C

Gene:
BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q13.1
Genomic location:
Preferred name:
NM_000059.4(BRCA2):c.8331+2T>C
HGVS:
  • NC_000013.11:g.32363535T>C
  • NG_012772.3:g.53056T>C
  • NM_000059.4:c.8331+2T>CMANE SELECT
  • NM_001406719.1:c.8235+2T>C
  • NM_001406720.1:c.8331+2T>C
  • NM_001406721.1:c.3399+2T>C
  • NM_001406722.1:c.1914+2T>C
  • LRG_293t1:c.8331+2T>C
  • LRG_293:g.53056T>C
  • NC_000013.10:g.32937672T>C
  • NM_000059.3:c.8331+2T>C
  • NM_000059.4:c.8331+2T>C
Links:
dbSNP: rs398122602
NCBI 1000 Genomes Browser:
rs398122602
Molecular consequence:
  • NM_000059.4:c.8331+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406719.1:c.8235+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406720.1:c.8331+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406721.1:c.3399+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406722.1:c.1914+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
Observations:
1

Condition(s)

Name:
Hereditary breast ovarian cancer syndrome
Synonyms:
Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000587947Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)
no assertion criteria provided
Pathogenic
(Jan 31, 2014)
germlineresearch

SCV000759096Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 16, 2024)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV002025847National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Nov 16, 2021)
germlineclinical testing

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

SCV004848283Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Oct 14, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing, research
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway.

Heramb C, Wangensteen T, Grindedal EM, Ariansen SL, Lothe S, Heimdal KR, Mæhle L.

Hered Cancer Clin Pract. 2018;16:3. doi: 10.1186/s13053-017-0085-6.

PubMed [citation]
PMID:
29339979
PMCID:
PMC5761139
See all PubMed Citations (10)

Details of each submission

From Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587947.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000759096.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change affects a donor splice site in intron 18 of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 24504028, 25186627, 29339979, 29446198, 29487695). ClinVar contains an entry for this variant (Variation ID: 267692). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

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

From National Health Laboratory Service, Universitas Academic Hospital and University of the Free State, SCV002025847.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848283.1

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

Description

The c.8331+2T>C variant in BRCA2 has been reported in at least 2 probands with BRCA2-related cancer (Cunningham 2014, Tung 2015). It was absent from large population studies, but has been reported in ClinVar (Variation ID: 267692). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies confirm that this variant leads to abnormal splicing (Fraile-Bethencourt 2017). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer (HBOC). ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.

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

Last Updated: Jan 13, 2025