NM_000059.4(BRCA2):c.1813dup (p.Ile605fs) AND Breast-ovarian cancer, familial, susceptibility to, 2

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

Germline classification:: Pathogenic (17 submissions)
Last evaluated:: Apr 22, 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:: RCV000031343.40

Allele description

NM_000059.4(BRCA2):c.1813dup (p.Ile605fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.1813dup (p.Ile605fs)

Other names:

2034insA; 2041_2042insA; p.Ile605AsnfsX11

HGVS:

NC_000013.11:g.32333291dup
NG_012772.3:g.22812dup
NM_000059.4:c.1813dupMANE SELECT
NP_000050.3:p.Ile605fs
LRG_293:g.22812dup
NC_000013.10:g.32907420_32907421insA
NC_000013.10:g.32907428dup
NM_000059.3:c.1806dupA
NM_000059.3:c.1813dupA
NM_000059.4:c.1813dupA
U43746.1:n.2034_2035insA
U43746.1:n.2041_2042insA
p.I605NFS*11
p.I605NfsX11
p.Ile605Asnfs*11

Nucleotide change:

2040insA

Protein change:

I605fs

Links:

Breast Cancer Information Core (BIC) (BRCA2): 2034&base_change=ins A; Breast Cancer Information Core (BIC) (BRCA2): 2041&base_change=ins A; dbSNP: rs80359306

NCBI 1000 Genomes Browser:

rs80359306

Molecular consequence:

NM_000059.4:c.1813dup - frameshift variant - [Sequence Ontology: SO:0001589]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

Observations:

171

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000053947	Sharing Clinical Reports Project (SCRP)	no assertion criteria provided	Pathogenic (Oct 11, 2013)	germline	clinical testing
SCV000145951	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Pathogenic (May 29, 2002)	germline, somatic	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000195964	Michigan Medical Genetics Laboratories, University of Michigan	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000212013	Institute of Human Genetics, Medical University Innsbruck - BRCA-Tyrol	no assertion criteria provided (clinical testing)	Pathogenic (Feb 11, 2015)	germline	clinical testing
SCV000220297	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Pathogenic (May 8, 2014)	unknown	literature only	PubMed (7) [See all records that cite these PMIDs] 22729890, 22535016, 15024741, 9150150, 8665505, 21952622, 21324516 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV000282363	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015))	Pathogenic (Apr 22, 2016)	germline	curation	ENIGMA BRCA1/2 Classification Criteria (2015), Citation Link,
SCV000326619	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,
SCV000577948	Genologica Medica See additional submitters Servicio Andaluz de Salud, Hospital Universitario Virgen de la Victoria	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000746277	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2017)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000839914	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 25, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001428710	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 22, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002104297	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30715675, 25741868
SCV002579911	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002588853	BRCAlab, Lund University	no assertion criteria provided	Pathogenic (Aug 26, 2022)	germline	clinical testing
SCV004099179	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 27, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004846973	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 5, 2024)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 9150150, 9585613, 9667259, 11802209, 15070707, 18042939, 20104584, 21232165, 21324516, 21548014, 21952622, 22729890, 23199084, 24156927, 25072261, 28724667, 29433453, 33471991, 25741868
SCV005093814	Department of Human Genetics, Hannover Medical School	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 5, 2024)	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	yes	39	2	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	167	not provided	108544	not provided	clinical testing, curation
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	not provided	38	not provided	not provided	38	not provided	clinical testing
not provided	somatic	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
Ashkenazi, Western European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Caucasian	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
Caucasian Non Hispanic	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
Causasians	germline	yes	not provided	2	not provided	not provided	yes	clinical testing
Central/Eastern European	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
Latin American, Caribbean	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
Native American	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
Near Eastern	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European	germline	yes	29	not provided	not provided	not provided	not provided	clinical testing
Western European, Central/Eastern European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European, German, Cyech	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western Europeanan, Central/Eastern European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western, Central/Eastern European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management.

Heidemann S, Fischer C, Engel C, Fischer B, Harder L, Schlegelberger B, Niederacher D, Goecke TO, Doelken SC, Dikow N, Jonat W, Morlot S, Schmutzler RC, Arnold NK.

Breast Cancer Res Treat. 2012 Aug;134(3):1229-39. doi: 10.1007/s10549-012-2050-4. Epub 2012 Apr 26.

PubMed [citation]

PMID:: 22535016

BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian cancer in the Czech Republic.

Foretova L, Machackova E, Navratilova M, Pavlu H, Hruba M, Lukesova M, Valik D.

Hum Mutat. 2004 Apr;23(4):397-8.

PubMed [citation]

PMID:: 15024741

See all PubMed Citations (23)

Details of each submission

From Sharing Clinical Reports Project (SCRP), SCV000053947.5

#	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	38	not provided	not provided		not provided	not provided	not provided	not provided

From Breast Cancer Information Core (BIC) (BRCA2), SCV000145951.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	27	not provided	not provided	clinical testing	PubMed (1)
2	not provided	1	not provided	not provided	clinical testing	PubMed (1)
3	not provided	2	not provided	not provided	clinical testing	PubMed (1)
4	not provided	1	not provided	not provided	clinical testing	PubMed (1)
5	not provided	1	not provided	not provided	clinical testing	PubMed (1)
6	Ashkenazi, Western European	1	not provided	not provided	clinical testing	PubMed (1)
7	Caucasian	1	not provided	not provided	clinical testing	PubMed (1)
8	Caucasian	1	not provided	not provided	clinical testing	PubMed (1)
9	Caucasian Non Hispanic	2	not provided	not provided	clinical testing	PubMed (1)
10	Central/Eastern European	2	not provided	not provided	clinical testing	PubMed (1)
11	Latin American, Caribbean	2	not provided	not provided	clinical testing	PubMed (1)
12	Native American	2	not provided	not provided	clinical testing	PubMed (1)
13	Near Eastern	1	not provided	not provided	clinical testing	PubMed (1)
14	Western European	29	not provided	not provided	clinical testing	PubMed (1)
15	Western European, Central/Eastern European	1	not provided	not provided	clinical testing	PubMed (1)
16	Western European, German, Cyech	1	not provided	not provided	clinical testing	PubMed (1)
17	Western Europeanan, Central/Eastern European	1	not provided	not provided	clinical testing	PubMed (1)
18	Western, Central/Eastern European	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		27	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		2	not provided	not provided	not provided
4	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
5	somatic	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
6	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
7	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
8	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
9	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided
10	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided
11	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided
12	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided
13	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
14	germline	yes	not provided	not provided	not provided		29	not provided	not provided	not provided
15	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
16	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
17	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
18	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Michigan Medical Genetics Laboratories, University of Michigan, SCV000195964.1

#	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	yes	not provided	Blood	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, Medical University Innsbruck - BRCA-Tyrol, SCV000212013.1

#	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 Counsyl, SCV000220297.2

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

#	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 Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), SCV000282363.1

#	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, SCV000326619.4

#	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	167	not provided

From Genologica Medica, SCV000577948.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Causasians	not provided	not provided	yes	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	Blood	not provided		not provided	not provided	2	not provided

From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000746277.1

#	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	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000839914.1

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

Description

The c.1813dup (p.Ile605Asnfs*11) variant in the BRCA2 gene has been detected in multiple patients with breast and/or ovarian cancer [referred as 2034insA and 2041insA in PMID 9150150, 21324516, 22535016] and prostate cancer [PMID 21952622].This variant has been reported in four individuals from the ExAC database (http://exac.broadinstitute.org/variant/22-29091226-TA-T). This one bp duplication in exon 10 results in a frameshift and the creation of a premature stop codon. This variant is expected to result in a loss of function of the protein. It is thus 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 Institute of Human Genetics, University of Leipzig Medical Center, SCV001428710.3

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

Description

Criteria applied: PVS1,PS4,PM5_STR

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

From University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM), SCV002104297.2

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

From MGZ Medical Genetics Center, SCV002579911.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	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		7	not provided	not provided	not provided

From BRCAlab, Lund University, SCV002588853.1

#	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	2	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV004099179.1

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

Description

PVS1, PM2, PS4

#	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 All of Us Research Program, National Institutes of Health, SCV004846973.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (19)

Description

This variant inserts 1 nucleotide in exon 10 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2034insA, 2040insA, 2041insA, 2041dupA, 2041_2042insA, c.1813insA and c.1806dupA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in a breast cancer case-control meta-analysis in 20 cases and 1 unaffected control, which is estimated to have an odds ratio for pathogenicity of OR=17.689 (95%CI 2.374 to 131.809; p-value<0.001) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001802) and also has been reported in individuals affected with breast, ovarian, pancreatic, prostate and neuroendocrine cancers (PMID: 9150150, 9667259, 18042939, 20104584, 21324516, 21952622, 22729890, 25072261, 28724667, 29433453) and suspected hereditary breast and ovarian cancer families (PMID: 11802209, 21232165, 24156927). In one family, this variant was reported in 11 women affected with breast cancer across three generations (PMID: 9150150). This variant also has been detected in two compound heterozygous individuals with a second pathogenic BRCA2 mutation who exhibited clinical features consistent with Fanconi anemia (PMID: 15070707, 21548014). Haplotype analysis suggests that this variant may be a founder mutation and is common in people of German ancestry (PMID: 9585613, 23199084). This variant has been identified in 3/232106 chromosomes 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		2	not provided	not provided	not provided

From Department of Human Genetics, Hannover Medical School, SCV005093814.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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