NM_000059.4(BRCA2):c.1813dup (p.Ile605fs) AND not provided

Germline classification:: Pathogenic (15 submissions)
Last evaluated:: Mar 1, 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:: RCV000160269.55

Allele description [Variation Report for NM_000059.4(BRCA2):c.1813dup (p.Ile605fs)]

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:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000210718	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 9, 2020)	germline	clinical testing	Citation Link,
SCV000296732	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (May 18, 2023)	unknown	clinical testing	PubMed (16) [See all records that cite these PMIDs] 22535016, 21324516, 22729890, 8665505, 29433453, 28324225, 33471991, 36169650, 30257646, 32606146, 23199084, 21232165, 9150150, 20104584, 26467025, 26295337
SCV000591772	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV001247641	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2024)	germline	clinical testing	Citation Link,
SCV001447436	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001450011	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 23, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001797345	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001905821	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001968680	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002019152	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 26, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002761148	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004035905	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	criteria provided, single submitter (Hauer et al. (Genet Med. 2018))	Pathogenic (Sep 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004225753	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 19, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21324516, 21952622, 22729890, 29446198, 9150150, 25741868
SCV004562779	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Mar 23, 2023)	germline	clinical testing	Citation Link,
SCV005199775	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 27, 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	unknown	yes	4	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	23	not provided	not provided	1	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

Mutations of the BRCA2 gene in ovarian carcinomas.

Takahashi H, Chiu HC, Bandera CA, Behbakht K, Liu PC, Couch FJ, Weber BL, LiVolsi VA, Furusato M, Rebane BA, Cardonick A, Benjamin I, Morgan MA, King SA, Mikuta JJ, Rubin SC, Boyd J.

Cancer Res. 1996 Jun 15;56(12):2738-41.

PubMed [citation]

PMID:: 8665505

See all PubMed Citations (20)

Details of each submission

From GeneDx, SCV000210718.11

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

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with hereditary breast and ovarian cancer (Frank 1998, Foretova 2004, Tai 2007, Kote-Jarai 2011, Becker 2012, Blay 2013, Pritzlaff 2017, Ibrahim 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 21952622, 22535016, 9150150, 15024741, 18489799, 28324225, 30715675, 21324516, 23683081, 20104584, 25685387, 26834852, 22729890, 27225637, 27167707, 28008555, 22382806, 28873162, 28503720, 28664449, 28651617, 25085752, 23199084, 29433453, 21232165, 15689453, 9667259, 9585613, 25072261, 18042939, 28831036, 28724667, 29909963, 30720863, 28843361, 30014164, 30702160, 30322717, 30309722, 30257646, 21548014, 15070707, 28726808, 31454914, 26689913, 32318955, 31447099, 29176636, 32581362)

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000296732.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

The BRCA2 c.1813dup (p.Ile605Asnfs*11) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in affected individuals with breast and/or ovarian cancer (PMIDs: 9150150 (1997), 21324516 (2011), 22729890 (2012), 28324225 (2017), 30257646 (2018), and 36169650 (2022)). In a large scale breast cancer association study, it was found in individuals with breast cancer as well as a control (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). It has also been reported in individuals with prostate cancer (PMIDs: 29433453 (2018) and 32606146 (2020)). Based on the available information, this variant is classified as pathogenic.

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591772.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

Description

The BRCA2 p.Ile605AsnfsX11 variant was identified in 8 of 22770 proband chromosomes (frequency: 0.00035) from individuals or families with Breast, Ovarian, or Prostate cancer (Becker, 2012; Heidemann, 2012; Janavicius, 2010; Kote-Jarai, 2011; Schubert, 1997; Zhang, 2011). The variant was shown to segregate in at least nine affected individuals with breast cancer (Schubert, 1997; Heidemann, 2012). The variant was also identified in dbSNP (ID: rs80359306) â€šÃ„ÃºWith pathogenic alleleâ€šÃ„Ã¹, HGMD, the BIC database (75X with class 5 clinical importance), and UMD (18X as a causal variant). The c.1813dupA duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 605 and leads to a premature stop codon 11 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

#	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		4	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001247641.25

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	16	not provided	not provided	clinical testing	not provided

Description

BRCA2: PVS1, PS4, PM2

#	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		16	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447436.1

#	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	1	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001450011.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	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		6	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV001797345.1

#	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 Laboratory, Department of Pathology, Netherlands Cancer Institute - VKGL Data-share Consensus, SCV001905821.1

#	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, SCV001968680.1

#	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 Revvity Omics, Revvity, SCV002019152.3

#	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 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002761148.3

#	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 Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, SCV004035905.1

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

Description

This variant has been identified by standard clinical testing. Breast-ovarian cancer, familial, susceptibility to, 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 Mayo Clinic Laboratories, Mayo Clinic, SCV004225753.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (6)

Description

PP5, PM2, PS4_moderate, PVS1

#	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		3	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004562779.1

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

Description

The BRCA2 c.1813dup; p.Ile605AsnfsTer11 variant (rs80359306), also known as 2041insA and 2034insA, is reported in the literature in several individuals with HBOC-related cancers (Becker 2012, Foretova 2004, Ibrahim 2018, Zhang 2011), and was demonstrated to segregate with disease in a large German family (Schubert 1997). This variant has also been reported in patients with prostate and other cancers (Ibrahim 2018, Kote-Jarai 2011). This variant is reported in ClinVar and is classified as pathogenic by an expert panel (Variation ID: 37762). This variant is only found on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Functional data indicate that cell lines derived from patients harboring the c.1813dup variant are more susceptible than wild-type to radiation induced chromosomal abnormalities (Becker 2012). Based on available information, the p.Ile605AsnfsTer11 variant is considered to be pathogenic. REFERENCES Becker et al. A 24-color metaphase-based radiation assay discriminates heterozygous BRCA2 mutation carriers from controls by chromosomal radiosensitivity. Breast Cancer Res Treat. 2012; 135(1): 167-175. PMID: 22729890. Foretova et al. BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian cancer in the Czech Republic. Hum Mutat. 2004 Apr; 23(4): 397-398. PMID: 15024741. Ibrahim M et al. Male BRCA mutation carriers: clinical characteristics and cancer spectrum. BMC Cancer. 2018 Feb 13;18(1):179. PMID: 29433453. Kote-Jarai et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011; 105(8): 1230-1234. PMID: 21952622. Schubert et al. BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. Am J Hum Genet. 1997; 60(5): 1031-1040. PMID: 9150150. Zhang et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011; 121(2): 353-357. PMID: 21324516.

#	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 Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005199775.1

#	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 13, 2024

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