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NM_000059.4(BRCA2):c.9253dup (p.Thr3085fs) AND not provided

Germline classification:
Pathogenic (6 submissions)
Last evaluated:
Feb 6, 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:
RCV000045760.24

Allele description [Variation Report for NM_000059.4(BRCA2):c.9253dup (p.Thr3085fs)]

NM_000059.4(BRCA2):c.9253dup (p.Thr3085fs)

Gene:
BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
13q13.1
Genomic location:
Preferred name:
NM_000059.4(BRCA2):c.9253dup (p.Thr3085fs)
HGVS:
  • NC_000013.11:g.32380142dup
  • NG_012772.3:g.69663dup
  • NM_000059.4:c.9253dupMANE SELECT
  • NP_000050.3:p.Thr3085fs
  • LRG_293t1:c.9253dup
  • LRG_293:g.69663dup
  • NC_000013.10:g.32954272_32954273insA
  • NC_000013.10:g.32954279dup
  • NM_000059.3:c.9253dup
  • NM_000059.3:c.9253dupA
  • NM_000059.4:c.9253dupA
  • U43746.1:n.9481_9482insA
  • p.T3085NFS*26
  • p.T3085NfsX26
  • p.Thr3085Asnfs*26
Nucleotide change:
9481insA
Protein change:
T3085fs
Links:
Breast Cancer Information Core (BIC) (BRCA2): 9481&base_change=ins A; dbSNP: rs80359752
NCBI 1000 Genomes Browser:
rs80359752
Molecular consequence:
  • NM_000059.4:c.9253dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000210800GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Pathogenic
(Sep 11, 2020)
germlineclinical testing

Citation Link,

SCV000809461Gharavi Laboratory, Columbia University
no assertion criteria provided

(ACMG Guidelines, 2015)
Pathogenic
(Sep 16, 2018)
germlineresearch

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

SCV000889181Quest Diagnostics Nichols Institute San Juan Capistrano
criteria provided, single submitter

(Quest Diagnostics criteria)
Pathogenic
(Oct 11, 2020)
unknownclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001554114Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Pathogenicunknownclinical testing

SCV001926450Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided
Pathogenicgermlineclinical testing

SCV004243077Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 6, 2024)
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, research
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Germline pathogenic variants identified in women with ovarian tumors.

Carter NJ, Marshall ML, Susswein LR, Zorn KK, Hiraki S, Arvai KJ, Torene RI, McGill AK, Yackowski L, Murphy PD, Xu Z, Solomon BD, Klein RT, Hruska KS.

Gynecol Oncol. 2018 Dec;151(3):481-488. doi: 10.1016/j.ygyno.2018.09.030. Epub 2018 Oct 12.

PubMed [citation]
PMID:
30322717

Comprehensive analysis of serum tumor markers and BRCA1/2 germline mutations in Chinese ovarian cancer patients.

Deng H, Chen M, Guo X, Heng J, Xu X, Peng L, Jiang H, Li G, Day JX, Li J, Shan D, Li Y, Zhou Y, Liu B, Dai L, Wang X, Wang J.

Mol Genet Genomic Med. 2019 Jun;7(6):e672. doi: 10.1002/mgg3.672. Epub 2019 Apr 10.

PubMed [citation]
PMID:
30972954
PMCID:
PMC6565576
See all PubMed Citations (10)

Details of each submission

From GeneDx, SCV000210800.10

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

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as 9481insA, 9481dupA, and 9474insA; This variant is associated with the following publications: (PMID: 22798144, 23034506, 16455195, 26287763, 21120943, 25330149, 30702160, 30322717, 32854451, 23569316, 11920643, 20104584, 19656164, 18824701, 11389159, 16683254, 21952622, 26681312, 25863477, 22720145, 28008555, 27836010, 28152038, 11802209, 7627958, 30972954, 29310832, 28724667, 29915322, 29339979, 30720243, 31396961, 29625052, 31447099, 32832836)

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

From Gharavi Laboratory, Columbia University, SCV000809461.1

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000889181.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This frameshift variant causes the premature termination of BRCA2 protein synthesis. In the published literature, it has been reported in individuals affected with breast and/or ovarian cancer, prostate cancer, and esophageal cancer (PMIDs: 11389159 (2001), 21952622 (2011), 22798144 (2012), 29915322 (2018), 30322717 (2018), 31396961 (2019), 30702160 (2019), and 30972954 (2019)). 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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001554114.1

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

Description

The BRCA2 p.Thr3085AsnfsX26 variant was identified in 13 of 20330 proband chromosomes (frequency: 0.0006) from German, Danish, Korean, American, and British individuals or families with (sporadic, high risk, early onset, or male) breast cancer, sporadic or familial ovarian cancer or prostate cancer (Meindl_2002_11802209, Bergthorsson_2001_11389159, Kang_2015_25863477 , Kim_2012_22798144, Pal_2015_26287763 , Pritzlaff_2016_28008555, Kote-Jarai_2011_21952622, Rebbeck_2016_27836010, Borg_2010_20104584, Cybulski_2015_25330149). In a study looking at transheterozygosity (inheritance of pathogenic mutations in both BRCA1 and BRCA2), the variant was identified in 1 Italian proband with breast cancer, co-occurring with BRCA1 c.3228_3229delAG (Rebbeck_2016_27836010). The variant was also identified in dbSNP (ID: rs80359752) “With Pathogenic allele”, ClinVar (classified pathogenic, reviewed by an expert panel (2016); submitters: pathogenic by ENIGMA, CIMBA, Fulgent Genetics, Ambry Genetics, GeneDx, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano, Invitae, Dept. of Medical Genetics (Oslo University Hospital), BIC and SCRP (Sharing Clinical Reports Project); and likely pathogenic by Counsyl), Clinvitae (4x), GeneInsight-COGR (classified pathogenic by 2 clinical laboratories), LOVD 3.0 (1x), UMD-LSDB (5x causal), BIC Database (19x, with clinical importance, class 5 (pathogenic)), ARUP Laboratories (5-definitely pathogenic), Zhejiang Colon Cancer Database; the variant was not identified in Cosmic, MutDB, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.9253dupA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3085 and leads to a premature stop codon at position 3110. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001926450.1

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

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV004243077.1

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

Last Updated: Feb 1, 2025