NM_000059.3(BRCA2):c.6275_6276delTT (p.Leu2092Profs) AND Hereditary breast and ovarian cancer syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Dec 26, 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:: RCV000044884.11

Allele description

NM_000059.3(BRCA2):c.6275_6276delTT (p.Leu2092Profs)

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.6275_6276delTT (p.Leu2092Profs)

Other names:

6503_6504delTT

HGVS:

NC_000013.11:g.32340630_32340631delTT
NG_012772.3:g.30151_30152delTT
NM_000059.3:c.6275_6276delTT
NP_000050.2:p.Leu2092Profs
LRG_293t1:c.6275_6276delTT
LRG_293:g.30151_30152delTT
LRG_293p1:p.Leu2092Profs
NC_000013.10:g.32914767_32914768delTT
NM_000059.3:c.6275_6276del
U43746.1:n.6503_6504delTT
p.L2092Pfs*7
p.L2092PfsX7
p.Leu2092Profs*7

Nucleotide change:

6503delTT

Links:

Breast Cancer Information Core (BIC) (BRCA2): 6503&base_change=del TT; OMIM: 600185.0002; dbSNP: rs11571658

NCBI 1000 Genomes Browser:

rs11571658

Allele Frequency:

0.00002(-)

Molecular consequence:

NM_000059.3:c.6275_6276delTT - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000072897	Invitae	criteria provided, single submitter (Nykamp K et al. (Genet Med 2017))	Pathogenic (Dec 26, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21324516, 20736950, 8524414, 22006311, 23199084, 22009639, 28492532
SCV000586966	Cancer 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)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000587833	Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)	no assertion criteria provided	Pathogenic (Jan 31, 2014)	germline	research
SCV000588108	Department of Pathology and Molecular Medicine,Queen's University - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000592039	Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 12, 2013)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12161611, 16616110, 20736950, 10090482, 21324516, 10227398, 12955716, 9537231, 25741868
SCV000694953	Integrated Genetics/Laboratory Corporation of America	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 22, 2016)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8896551, 10227398, 21324516, 20859677, 9585608 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of the breast cancer susceptibility gene BRCA2.

Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G.

Nature. 1995 Dec 21-28;378(6559):789-92. Erratum in: Nature 1996 Feb 22;379(6567):749.

PubMed [citation]

PMID:: 8524414

Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.

Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, Roeb W, Agnew KJ, Stray SM, Wickramanayake A, Norquist B, Pennington KP, Garcia RL, King MC, Swisher EM.

Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. doi: 10.1073/pnas.1115052108. Epub 2011 Oct 17.

PubMed [citation]

PMID:: 22006311
PMCID:: PMC3207658

See all PubMed Citations (17)

Details of each submission

From Invitae, SCV000072897.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Leu2092Profs*7) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs11571658, ExAC 0.009%). This variant has been reported in individuals affected with breast, ovarian, and prostate cancer (PMID: 8524414, 22009639, 21324516, 22006311, 20736950, 23199084), and has been proposed to be a European founder variant (PMID: 23199084). This variant is also known as 6503delTT in the literature. ClinVar contains an entry for this variant (Variation ID: 9318). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency - The Canadian Open Genetics Repository (COGR), SCV000586966.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587833.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Molecular Medicine,Queen's University - The Canadian Open Genetics Repository (COGR), SCV000588108.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592039.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Integrated Genetics/Laboratory Corporation of America, SCV000694953.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: The BRCA2 c.6275_6276delTT (p.Leu2092Profs) 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.p.N2135fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/120912 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in numerous Br/Ov cancer patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 30, 2018

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