NM_000059.4(BRCA2):c.7934del (p.Arg2645fs) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 28, 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:: RCV000257923.24

Allele description [Variation Report for NM_000059.4(BRCA2):c.7934del (p.Arg2645fs)]

NM_000059.4(BRCA2):c.7934del (p.Arg2645fs)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.7934del (p.Arg2645fs)

Other names:

NP_000050.3:p.Arg2645AsnfsTer3

HGVS:

NC_000013.11:g.32362651del
NG_012772.3:g.52172del
NM_000059.4:c.7934delMANE SELECT
NP_000050.3:p.Arg2645fs
LRG_293:g.52172del
NC_000013.10:g.32936788del
NC_000013.10:g.32936788delG
NM_000059.3:c.7934delG
NM_000059.4:c.7934del
U43746.1:n.8162delG
p.Arg2645Asnfs*3
p.R2645NFS*3

Nucleotide change:

8162delG

Protein change:

R2645fs

Links:

Breast Cancer Information Core (BIC) (BRCA2): 8162&base_change=del G; dbSNP: rs80359688

NCBI 1000 Genomes Browser:

rs80359688

Molecular consequence:

NM_000059.4:c.7934del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Hereditary breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000073361	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 20104584, 8988179, 22638694, 23885733, 24728189, 26577449, 26915939, 28492532
SCV000587922	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
SCV000695109	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 12, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24728189, 8988179, 21204799 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV002025834	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 19, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	21	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

Borg A, Haile RW, Malone KE, Capanu M, Diep A, Törngren T, Teraoka S, Begg CB, Thomas DC, Concannon P, Mellemkjaer L, Bernstein L, Tellhed L, Xue S, Olson ER, Liang X, Dolle J, Børresen-Dale AL, Bernstein JL.

Hum Mutat. 2010 Mar;31(3):E1200-40. doi: 10.1002/humu.21202.

PubMed [citation]

PMID:: 20104584
PMCID:: PMC2928257

CYP2D6 genotyping and use of antidepressants in breast cancer patients: test development for clinical application.

van der Merwe N, Bouwens CS, Pienaar R, van der Merwe L, Yako YY, Geiger DH, Kotze MJ.

Metab Brain Dis. 2012 Sep;27(3):319-26. doi: 10.1007/s11011-012-9312-z. Epub 2012 May 26.

PubMed [citation]

PMID:: 22638694
PMCID:: PMC3505529

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000073361.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Arg2645Asnfs*3) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8988179, 22638694, 23885733, 24728189, 26577449, 26915939). This variant is also known as 8162delG. ClinVar contains an entry for this variant (Variation ID: 52440). 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 Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587922.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695109.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: The BRCA2 c.7934delG (p.Arg2645Asnfs) variant located in the helical domain (Interpro) 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. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals. The variant of interest has been indicated to be an Afrikaner founder mutation. 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.

#	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 National Health Laboratory Service, Universitas Academic Hospital and University of the Free State, SCV002025834.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	21	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	yes	not provided	not provided	not provided		21	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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