NM_000059.4(BRCA2):c.4449del (p.Asp1484fs) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Sep 8, 2016
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000031485.27

Allele description [Variation Report for NM_000059.4(BRCA2):c.4449del (p.Asp1484fs)]

NM_000059.4(BRCA2):c.4449del (p.Asp1484fs)

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.4449del (p.Asp1484fs)

HGVS:

NC_000013.11:g.32338804del
NG_012772.3:g.28325del
NM_000059.4:c.4449delMANE SELECT
NP_000050.3:p.Asp1484fs
LRG_293:g.28325del
NC_000013.10:g.32912941del
NC_000013.10:g.32912941delA
NM_000059.3:c.4449delA
NM_000059.4:c.4449del
NM_000059.4:c.4449delA
U43746.1:n.4677delA
p.Asp1484Thrfs*2
p.D1484Tfs*2
p.D1484TfsX2

Nucleotide change:

4677delA

Links:

Breast Cancer Information Core (BIC) (BRCA2): 4677&base_change=del A; dbSNP: rs80359448

NCBI 1000 Genomes Browser:

rs80359448

Molecular consequence:

NM_000059.4:c.4449del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Breast-ovarian cancer, familial, susceptibility to, 2 (BROVCA2)
Synonyms:: Breast-ovarian cancer, familial 2
Identifiers:: MONDO: MONDO:0012933; MedGen: C2675520; Orphanet: 145; OMIM: 612555

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
SCV000054090	Sharing Clinical Reports Project (SCRP)	no assertion criteria provided	Pathogenic (Mar 19, 2012)	germline	clinical testing
SCV000146423	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Pathogenic (May 29, 2002)	germline	clinical testing
SCV000300747	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015))	Pathogenic (Sep 8, 2016)	germline	curation	ENIGMA BRCA1/2 Classification Criteria (2015), Citation Link,
SCV000327035	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016)	Pathogenic (Oct 2, 2015)	germline	clinical testing	CIMBA_Mutation_Classification_guidelines_May16.pdf, Citation Link,
SCV000488692	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Pathogenic (May 27, 2016)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11802209, 20104584 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV000733256	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV000744455	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Sep 21, 2015)	germline	clinical testing	Citation Link,
SCV002556648	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11802209, 20104584, 25111659, 27767231, 25741868
SCV002579083	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 30, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004845682	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 11802209, 16683254, 20104584, 25111659, 27767231, 29053726, 29446198, 33471991, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	26	not provided	108544	not provided	clinical testing, curation
not provided	germline	not provided	4	not provided	not provided	4	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
German	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population.

Meindl A; German Consortium for Hereditary Breast and Ovarian Cancer..

Int J Cancer. 2002 Feb 1;97(4):472-80.

PubMed [citation]

PMID:: 11802209

A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting.

van der Hout AH, van den Ouweland AM, van der Luijt RB, Gille HJ, Bodmer D, Brüggenwirth H, Mulder IM, van der Vlies P, Elfferich P, Huisman MT, ten Berge AM, Kromosoeto J, Jansen RP, van Zon PH, Vriesman T, Arts N, Lange MB, Oosterwijk JC, Meijers-Heijboer H, Ausems MG, Hoogerbrugge N, Verhoef S, et al.

Hum Mutat. 2006 Jul;27(7):654-66.

PubMed [citation]

PMID:: 16683254

See all PubMed Citations (9)

Details of each submission

From Sharing Clinical Reports Project (SCRP), SCV000054090.5

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	4	not provided	not provided		not provided	not provided	not provided	See 1

Co-occurrences

#	Zygosity	Alleles	Number of Observations
1	SingleHeterozygote	BRCA1:4016G>T (Q1299H)	1

From Breast Cancer Information Core (BIC) (BRCA2), SCV000146423.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided
2	not provided	1	not provided	not provided	clinical testing	not provided
3	German	1	not provided	not provided	clinical testing	not provided
4	Western European	2	not provided	not provided	clinical testing	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		1	not provided	not provided	not provided
2	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), SCV000300747.2

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

Description

Variant allele predicted to encode a truncated non-functional protein.

#	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 Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge, SCV000327035.4

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

#	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	26	not provided

From Counsyl, SCV000488692.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV000733256.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	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 Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV000744455.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	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 Genetics and Molecular Pathology, SA Pathology, SCV002556648.2

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

Description

The BRCA2:c.4449del variant is classified as PATHOGENIC (ENIGMA criteria 2017) BRCA2:c.4449del is a single nucleotide deletion in exon 11 predicted to encode a frame-shift in translation of the mature mRNA with consequent premature termination of protein synthesis at codon 2 of the frame-shift, or 1485 (BRCA2:p.(Asp1484ThrfsTer2) using NP_000050.3. This is predicted to result in absent BRCA2 protein due to nonsense mediated decay (NMD). If NMD is escaped, this variant is expected to encode a truncated protein. Variants of this type are widely accepted to be pathogenic. This variant has been reviewed by the ENIGMA expert review panel: ENIGMA determine BRCA2:c.4449del as consistent with an IARC Class 5 variant equivalent to ACMG classification of Pathogenic. This variant is also reported in the literature as BRCA2 4677delA using legacy nomenclature. BRCA2:c.4449del has been reported in multiple unrelated individuals with breast, prostate, or ovarian cancer (Meindl et al., 2002, PMID:11802209, Borg et al., 2010, PMID:20104584, Weren et al., 2017, PMID:27767231, Maier et al., 2014, PMID:25111659). BRCA2:c.4449del (rs80359448) is absent from population databases and is not on record in FLOSSIES. BRCA2:c.4449del is on record in ClinVar (Variation ID:37904) reported by multiple clinical laboratories without conflict as pathogenic in association with hereditary breast and ovarian cancer syndrome. This variant is listed in HGMD as ‘disease causing mutation’ in association with breast and/or ovarian cancer (Accession:CD021793).

#	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 MGZ Medical Genetics Center, SCV002579083.1

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

From All of Us Research Program, National Institutes of Health, SCV004845682.1

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

Description

This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least five individuals affected with breast, ovarian or prostate cancer (PMID: 20104584, 25111659, 27767231, 29053726, 33471991; Leiden Open Variation Database DB-ID BRCA2_001679; Color internal data), in several suspected hereditary breast and ovarian cancer families (PMID: 11802209, 16683254, 29446198), and in one unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001679). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 13, 2024

Relating variation to medicine