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NM_000059.4(BRCA2):c.8331+2T>C AND not provided

Germline classification:
Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:
Aug 15, 2023
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:
RCV000519723.17

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]

Condition(s)

Synonyms:
none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000617474GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Likely pathogenic
(Dec 24, 2020)
germlineclinical testing

Citation Link,

SCV003814482Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jan 10, 2023)
germlineclinical testing

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

SCV004024416Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Aug 15, 2023)
germlineclinical testing

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

SCV004220598Quest Diagnostics Nichols Institute San Juan Capistrano
criteria provided, single submitter

(Quest Diagnostics criteria)
Pathogenic
(Jan 20, 2023)
unknownclinical testing

PubMed (17)
[See all records that cite these PMIDs]

SCV005197324Clinical Genetics Laboratory, Skane University Hospital Lund
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(May 8, 2023)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]
PMID:
25186627

Functional classification of DNA variants by hybrid minigenes: Identification of 30 spliceogenic variants of BRCA2 exons 17 and 18.

Fraile-Bethencourt E, Díez-Gómez B, Velásquez-Zapata V, Acedo A, Sanz DJ, Velasco EA.

PLoS Genet. 2017 Mar;13(3):e1006691. doi: 10.1371/journal.pgen.1006691.

PubMed [citation]
PMID:
28339459
PMCID:
PMC5384790
See all PubMed Citations (18)

Details of each submission

From GeneDx, SCV000617474.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Canonical splice site variant expected to result in aberrant splicing, however published functional and RNA studies are conflicting showing both aberrant splicing resulting in skipping of exon 18 and normal splicing, as well as both aberrant and wildtype transcript expression (Fraile-Bethencourt 2017, Gelli 2019, Wangensteen 2019, Wai 2020); Not observed in large population cohorts (Lek 2016); Also known as 8559+2T>G; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer referred for genetic testing at GeneDx and in published literature (Cunningham 2014, Tung 2015, Kwong 2018, Fanale 2020, Rumford 2020); This variant is associated with the following publications: (PMID: 29487695, 32123317, 25186627, 28339459, 30832263, 31143303, 24504028, 29339979, 29446198, 30702160, 31131967, 32854451, 32098980, 31209999, 32380732)

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

From Revvity Omics, Revvity, SCV003814482.2

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

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV004024416.2

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004220598.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (17)

Description

This variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 24504028 (2014)), and in individuals with breast cancer (PMID: 25186627 (2015), 29487695 (2018), 30130155 (2018), 30702160 (2019), 32854451 (2020), 35464868 (2022)). In large breast cancer association studies, this variant was found in individuals affected with breast cancer as well as unaffected individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/BRCA2). Functional splicing assays demonstrate this this variant causes aberrant splicing and skipping of exon 18 and/or partial exon 17 and exon 18, creating a premature stop codon (PMID: 28339459 (2017), 30832263 (2019), 31143303 (2019), 33469799 (2021)). However, production of the normal transcript was also demonstrated (PMID: 30832263 (2019), 32123317 (2020), 33469799 (2021)). Based on the available information, this variant is classified as pathogenic.

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

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005197324.1

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

Last Updated: Jan 13, 2025