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NM_000059.4(BRCA2):c.7758G>A (p.Trp2586Ter) AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Pathogenic (Last evaluated: Mar 13, 2017)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000496860.1

Allele description

NM_000059.4(BRCA2):c.7758G>A (p.Trp2586Ter)

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.7758G>A (p.Trp2586Ter)
HGVS:
  • NC_000013.11:g.32357882G>A
  • NG_012772.3:g.47403G>A
  • NM_000059.3:c.7758G>A
  • NM_000059.4:c.7758G>AMANE SELECT
  • NP_000050.2:p.Trp2586Ter
  • NP_000050.3:p.Trp2586Ter
  • LRG_293t1:c.7758G>A
  • LRG_293:g.47403G>A
  • LRG_293p1:p.Trp2586Ter
  • NC_000013.10:g.32932019G>A
  • U43746.1:n.7986G>A
  • p.Trp2586X
Nucleotide change:
7986G>A
Protein change:
W2586*
Links:
dbSNP: rs80359004
NCBI 1000 Genomes Browser:
rs80359004
Molecular consequence:
  • NM_000059.3:c.7758G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000059.4:c.7758G>A - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

Condition(s)

Name:
Hereditary breast and ovarian cancer syndrome (HBOC)
Synonyms:
Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC)
Identifiers:
MONDO: MONDO:0003582; 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
SCV000587906Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)no assertion criteria providedPathogenic
(Jan 31, 2014)
germlineresearch

SCV000605818Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(Mar 13, 2017)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000695099Integrated Genetics/Laboratory Corporation of Americacriteria provided, single submitter
Pathogenic
(May 4, 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 providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedresearch
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

Outcome of unexpected adnexal neoplasia discovered during risk reduction salpingo-oophorectomy in women with germ-line BRCA1 or BRCA2 mutations.

Conner JR, Meserve E, Pizer E, Garber J, Roh M, Urban N, Drescher C, Quade BJ, Muto M, Howitt BE, Pearlman MD, Berkowitz RS, Horowitz N, Crum CP, Feltmate C.

Gynecol Oncol. 2014 Feb;132(2):280-6. doi: 10.1016/j.ygyno.2013.12.009. Epub 2013 Dec 12.

PubMed [citation]
PMID:
24333842
PMCID:
PMC3932113

Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction.

Callahan MJ, Crum CP, Medeiros F, Kindelberger DW, Elvin JA, Garber JE, Feltmate CM, Berkowitz RS, Muto MG.

J Clin Oncol. 2007 Sep 1;25(25):3985-90.

PubMed [citation]
PMID:
17761984
See all PubMed Citations (8)

Details of each submission

From Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587906.1

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

From Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine, SCV000605818.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (5)

Description

The p.Trp2586X variant in BRCA2 has been reported >5 individuals with BRCA2-asso ciated cancers (Meindl 2002, Callahan 2007, Conner 2014, Nahleh 2015, and Breast Cancer Information Core (BIC) database) and was absent from large population st udies. This nonsense variant leads to a premature termination codon at position 2586, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in heredi tary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel ( ClinVar SCV000301200.2). In summary, this variant meets criteria to be classifie d as pathogenic for HBOC in an autosomal dominant manner based upon absence in c ontrols and the predicted impact to the protein.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Integrated Genetics/Laboratory Corporation of America, SCV000695099.1

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

Description

Variant summary: The BRCA2 variant, c.7758G>A (p.Trp2586X) causes a nonsense mutation involving a conserved nucleotide resulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.

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

Last Updated: Apr 18, 2021