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NM_000059.3(BRCA2):c.3865_3868delAAAT (p.Lys1289Alafs) AND Hereditary breast and ovarian cancer syndrome

Germline classification:
Pathogenic (4 submissions)
Last evaluated:
Nov 1, 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:
RCV000044292.4

Allele description

NM_000059.3(BRCA2):c.3865_3868delAAAT (p.Lys1289Alafs)

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.3865_3868delAAAT (p.Lys1289Alafs)
HGVS:
  • NC_000013.11:g.32338220_32338223delAAAT
  • NG_012772.3:g.27741_27744delAAAT
  • NM_000059.3:c.3865_3868delAAAT
  • NP_000050.2:p.Lys1289Alafs
  • LRG_293t1:c.3865_3868delAAAT
  • LRG_293:g.27741_27744delAAAT
  • LRG_293p1:p.Lys1289Alafs
  • NC_000013.10:g.32912357_32912360delAAAT
  • NM_000059.3:c.3865_3868del
  • U43746.1:n.4093_4096del4
  • U43746.1:n.4093_4096delAAAT
  • p.Lys1289Alafs*3
Nucleotide change:
4093del4
Links:
Breast Cancer Information Core (BIC) (BRCA2): 4093&base_change=del 4; dbSNP: rs80359412
NCBI 1000 Genomes Browser:
rs80359412
Molecular consequence:
  • NM_000059.3:c.3865_3868delAAAT - 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
SCV000072305Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Apr 12, 2017)
germlineclinical testing

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

SCV000586946Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency - The Canadian Open Genetics Repository (COGR)
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Apr 18, 2017)
germlineclinical testing

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

SCV000693566GeneKor MSA,
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Nov 1, 2017)
germlineclinical testing

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

SCV000694727Integrated Genetics/Laboratory Corporation of America
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Sep 6, 2016)
germlineclinical testing

PubMed (5)
[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
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000072305.4

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

Description

This sequence change deletes 4 nucleotides in exon 11 of the BRCA2 mRNA (c.3865_3868delAAAT), causing a frameshift at codon 1289. This creates a premature translational stop signal (p.Lys1289Alafs*3) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic. This particular variant has been reported in the literature in individuals with familial breast and ovarian cancer (PMID: 11102978, 22729890, 20104584). This variant is also known as 4093delAAAT or 4093del4 in the literature. An experimental study has shown that patient-derived lymphocytes carrying this variant exhibit increased chromosomal radiosensitivity in metaphase-based radiation assay (PMID: 22729890). For these reasons, this variant has been classified as Pathogenic.

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

From Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency - The Canadian Open Genetics Repository (COGR), SCV000586946.1

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

From GeneKor MSA,, SCV000693566.1

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

From Integrated Genetics/Laboratory Corporation of America, SCV000694727.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: The c.3865_3868delAAAT (p.Lys1289Alafs) variant in the BRCA2 gene is a frameshift change predicted to cause a loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay, which is a known disease mechanism in HBOC. The variant has been reported in multiple affected individuals and is absent from the large control population dataset of EXAC. The results of the functional study have shown that patient-derived lymphocytes carrying this variant exhibit increased chromosomal radiosensitivity in metaphase-based radiation assay, confirming deleterious outcome for this variant (Becker_2012). Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic.

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

Last Updated: Sep 30, 2018