NM_000059.4(BRCA2):c.4478_4481del (p.Glu1493fs) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 18, 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:: RCV000195401.20

Allele description [Variation Report for NM_000059.4(BRCA2):c.4478_4481del (p.Glu1493fs)]

NM_000059.4(BRCA2):c.4478_4481del (p.Glu1493fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.4478_4481del (p.Glu1493fs)

Other names:

4706delAAAG; 4705del4; 4706_4709delAAAG

HGVS:

NC_000013.10:g.32912965_32912968del
NC_000013.11:g.32338829AAAG[1]
NG_012772.3:g.28350AAAG[1]
NM_000059.4:c.4478_4481delMANE SELECT
NP_000050.3:p.Glu1493fs
LRG_293:g.28350AAAG[1]
NC_000013.10:g.32912965_32912968del
NC_000013.10:g.32912966AAAG[1]
NC_000013.10:g.32912970_32912973del
NC_000013.10:g.32912970_32912973delAAAG
NM_000059.3:c.4478_4481delAAAG
NM_000059.4:c.4478_4481del
U43746.1:n.4706_4709delAAAG
p.E1493VFS*10
p.E1493VfsX10
p.Glu1493Valfs*10
p.Glu1493fs

Nucleotide change:

4706Del4

Protein change:

E1493fs

Links:

Breast Cancer Information Core (BIC) (BRCA2): 4705&base_change=del GAAA; Breast Cancer Information Core (BIC) (BRCA2): 4706&base_change=del AAAG; dbSNP: rs80359454

NCBI 1000 Genomes Browser:

rs80359454

Molecular consequence:

NM_000059.4:c.4478_4481del - frameshift variant - [Sequence Ontology: SO:0001589]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000072434	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 20104584, 8589730, 11179017, 15131399, 20927582, 21324516, 21952622, 22798144, 28492532
SCV000587714	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
SCV000588092	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]
SCV000694775	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 4, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8589730, 21324516, 22798144 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	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

Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer.

Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, Jack E, Vesprini DJ, Kuperstein G, Abrahamson JL, Fan I, Wong B, Narod SA.

Am J Hum Genet. 2001 Mar;68(3):700-10. Epub 2001 Feb 15.

PubMed [citation]

PMID:: 11179017
PMCID:: PMC1274482

See all PubMed Citations (10)

Details of each submission

From Invitae, SCV000072434.14

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

Description

This sequence change creates a premature translational stop signal (p.Glu1493Valfs*10) 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 present in population databases (rs776022857, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with female breast and ovarian cancer, male breast cancer, and prostate cancer (PMID: 8589730, 11179017, 15131399, 20927582, 21324516, 21952622, 22798144). This variant is also known as 4706del4. ClinVar contains an entry for this variant (Variation ID: 51653). 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), SCV000587714.1

#	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), SCV000588092.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694775.1

#	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 variant, c.4478_4481delAAAG (p.Glu1493Valfs), causes a frameshift resulting in a premature stop 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 clinical laboratories/databases cite the variant with a classification of "pathogenic." Therefore, 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

Last Updated: Apr 15, 2024

ClinVar

Relating variation to medicine