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NM_000059.3(BRCA2):c.1310_1313delAAGA (p.Lys437Ilefs) AND Hereditary breast and ovarian cancer syndrome

Germline classification:
Pathogenic (4 submissions)
Last evaluated:
Nov 15, 2017
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:
RCV000203644.7

Allele description

NM_000059.3(BRCA2):c.1310_1313delAAGA (p.Lys437Ilefs)

Gene:
BRCA2:BRCA2, DNA repair associated [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
13q13.1
Genomic location:
Preferred name:
NM_000059.3(BRCA2):c.1310_1313delAAGA (p.Lys437Ilefs)
Other names:
1529del4; 1537del4; 1537_1540delAAAG
HGVS:
  • NC_000013.11:g.32332788_32332791delAAGA
  • NG_012772.3:g.22309_22312delAAGA
  • NM_000059.3:c.1310_1313delAAGA
  • NP_000050.2:p.Lys437Ilefs
  • LRG_293t1:c.1310_1313delAAGA
  • LRG_293:g.22309_22312delAAGA
  • LRG_293p1:p.Lys437_Asp438delinsIlefs
  • NC_000013.10:g.32906925_32906928delAAGA
  • NG_012772.3:g.22300_22303delAAAG
  • NG_012772.3:g.22308_22311delAAAG
  • NM_000059.3:c.1301_1304delAAAG
  • NM_000059.3:c.1309_1312delAAAG
  • NM_000059.3:c.1310_1313del
  • U43746.1:n.1529_1532delAAAG
  • U43746.1:n.1537_1540delAAAG
  • U43746.1:n.1538_1541delAAGA
  • p.K437Ifs*22
  • p.K438IfsX22
  • p.Lys437Ilefs*22
Nucleotide change:
1538del4
Links:
Breast Cancer Information Core (BIC) (BRCA2): 1529&base_change=del AAAG; Breast Cancer Information Core (BIC) (BRCA2): 1537&base_change=del AAAG; Breast Cancer Information Core (BIC) (BRCA2): 1538&base_change=del AAGA; dbSNP: rs80359277
NCBI 1000 Genomes Browser:
rs80359277
Allele Frequency:
0.00001(-)
Molecular consequence:
  • NM_000059.3:c.1310_1313delAAGA - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Hereditary breast and ovarian cancer syndrome (HBOC)
Synonyms:
Hereditary breast and ovarian cancer
Identifiers:
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
SCV000071792Invitae
criteria provided, single submitter

(Nykamp K et al. (Genet Med 2017))
Pathogenic
(Nov 15, 2017)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000587590Research 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

SCV000591735Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 13, 2013)
germlineclinical testing

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

SCV000694532Integrated Genetics/Laboratory Corporation of America
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(May 1, 2017)
germlineclinical testing

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

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

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

Citations

PubMed

Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases.

Caputo S, Benboudjema L, Sinilnikova O, Rouleau E, BĂ©roud C, Lidereau R; French BRCA GGC Consortium.

Nucleic Acids Res. 2012 Jan;40(Database issue):D992-1002. doi: 10.1093/nar/gkr1160. Epub 2011 Dec 5.

PubMed [citation]
PMID:
22144684
PMCID:
PMC3245050

Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene.

Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Ponder BA, Stratton MR, Easton D.

Nat Genet. 1997 Jan;15(1):103-5.

PubMed [citation]
PMID:
8988179
See all PubMed Citations (12)

Details of each submission

From Invitae, SCV000071792.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Lys437Ilefs*22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80359277, ExAC 0.01%). Loss-of-function variants in BRCA2 are known to be pathogenic. This particular variant has been reported in the literature in numerous individuals and families affected with breast and/or ovarian cancer (PMID: 22144684, 18465347, 12955716, 8988179, 20683152, 25863477). This variant is also known as 1538del4 and 1529del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 37737). Loss-of-function variants in BRCA2 are known to be pathogenic (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 Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587590.1

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

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591735.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Integrated Genetics/Laboratory Corporation of America, SCV000694532.1

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

Description

Variant summary: The BRCA2 c.1310_1313delAAGA (p.Lys437Ilefs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.1456C>T (p.Gln486X) and c.1654delT (p.Ser552fs)). This variant was found in 1/120430 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in multiple HBOC patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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

Last Updated: Sep 30, 2018