NM_000059.4(BRCA2):c.5073dup (p.Trp1692fs) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Pathogenic (15 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:: RCV000031524.31

Allele description [Variation Report for NM_000059.4(BRCA2):c.5073dup (p.Trp1692fs)]

NM_000059.4(BRCA2):c.5073dup (p.Trp1692fs)

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.5073dup (p.Trp1692fs)

Other names:

5301_5302insA; p.Trp1692MetfsX3; p.Trp1692fs

HGVS:

NC_000013.11:g.32339428dup
NG_012772.3:g.28949dup
NM_000059.4:c.5073dupMANE SELECT
NP_000050.3:p.Trp1692fs
LRG_293:g.28949dup
NC_000013.10:g.32913558_32913559insA
NC_000013.10:g.32913565dup
NC_000013.10:g.32913565dupA
NM_000059.3:c.5073dupA
NM_000059.4:c.5073dup
NM_000059.4:c.5073dupA
U43746.1:n.5301_5302insA
p.Trp1692Metfs*3
p.W1692Mfs*3
p.W1692MfsX3

Nucleotide change:

5301insA

Protein change:

W1692fs

Links:

Breast Cancer Information Core (BIC) (BRCA2): 5301&base_change=ins A; dbSNP: rs80359479

NCBI 1000 Genomes Browser:

rs80359479

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000054129	Sharing Clinical Reports Project (SCRP)	no assertion criteria provided	Pathogenic (Oct 3, 2012)	germline	clinical testing
SCV000146530	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Pathogenic (May 29, 2002)	germline	clinical testing
SCV000220690	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Pathogenic (Sep 11, 2014)	unknown	literature only	PubMed (14) [See all records that cite these PMIDs] 14973102, 16683254, 11179017, 18819001, 21324516, 11938448, 12181777, 22866093, 14559878, 19912264, 24333842, 15131399, 19796187, 21559243 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV000282397	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,
SCV000327126	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,
SCV000591938	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
SCV000593745	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 30, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000605702	Department of Medical Genetics, Oslo University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000840551	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 12, 2018)	maternal	research	PubMed (1) [See all records that cite this PMID]
SCV001423223	GenomeConnect, ClinGen	no classification provided	not provided	unknown	phenotyping only
SCV001434850	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 12, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002004011	Molecular Endocrinology Laboratory, Christian Medical College	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28477318, 25741868
SCV002512263	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004243650	BRCAlab, Lund University	no assertion criteria provided	Pathogenic (Mar 2, 2020)	germline	clinical testing
SCV004845762	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 5, 2024)	germline	clinical testing	PubMed (23) [See all records that cite these PMIDs] 11179017, 11938448, 12181777, 14559878, 14973102, 15131399, 16683254, 18819001, 19052777, 19796187, 21324516, 21465317, 23977390, 24333842, 24728189, 25479140, 26026974, 26787237, 27741520, 28486781, 32022259, 33471991, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	16	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	15	not provided	not provided	15	not provided	clinical testing
not provided	germline	unknown	10	60	not provided	108544	not provided	clinical testing, curation
not provided	maternal	unknown	1	not provided	not provided	1	not provided	research
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, phenotyping only
Caucasian	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
Central/Eastern European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European	germline	yes	10	not provided	not provided	not provided	not provided	clinical testing
Western European, Malta	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic testing and first presymptomatic diagnosis in Moroccan families at high risk for breast/ovarian cancer.

Laarabi FZ, Jaouad IC, Ouldim K, Aboussair N, Jalil A, Gueddari BE, Benjaafar N, Sefiani A.

Oncol Lett. 2011 Mar;2(2):389-393. Epub 2011 Jan 21.

PubMed [citation]

PMID:: 22866093
PMCID:: PMC3410606

BRCA1 5272-1G>A and BRCA2 5374delTATG are founder mutations of high relevance for genetic counselling in breast/ovarian cancer families of Spanish origin.

Infante M, Durán M, Acedo A, Pérez-Cabornero L, Sanz DJ, García-González M, Beristain E, Esteban-Cardeñosa E, de la Hoya M, Teulé A, Vega A, Tejada MI, Lastra E, Miner C, Velasco EA.

Clin Genet. 2010 Jan;77(1):60-9. doi: 10.1111/j.1399-0004.2009.01272.x. Epub 2009 Nov 2.

PubMed [citation]

PMID:: 19912264

See all PubMed Citations (27)

Details of each submission

From Sharing Clinical Reports Project (SCRP), SCV000054129.6

#	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	15	not provided	not provided		not provided	not provided	not provided	not provided

From Breast Cancer Information Core (BIC) (BRCA2), SCV000146530.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	14	not provided	not provided	clinical testing	not provided
2	not provided	1	not provided	not provided	clinical testing	not provided
3	Caucasian	1	not provided	not provided	clinical testing	not provided
4	Caucasian	1	not provided	not provided	clinical testing	not provided
5	Central/Eastern European	1	not provided	not provided	clinical testing	not provided
6	Western European	10	not provided	not provided	clinical testing	not provided
7	Western European, Malta	1	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		14	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		1	not provided	not provided	not provided
5	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
6	germline	yes	not provided	not provided	not provided		10	not provided	not provided	not provided
7	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Counsyl, SCV000220690.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (14)

#	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), SCV000282397.1

#	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, SCV000327126.4

#	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	60	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591938.2

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

Description

The BRCA2 p.Trp1692MetfsX3 variant was identified in 10 of 5448 proband chromosomes (frequency: 0.002) from individuals or families with breast and ovarian cancer (Laarabi 2011, Lubinski 2004, Risch 2001, Suter 2004, Ottini 2009, de Juan 2015, Fernandes 2016, Hasmad 2016). It was also found as a de novo change in a patient who developed early onset breast cancer with no strong family history of the disease (Marshall 2009). The variant was identified in the following databases: dbSNP (ID: rs80359480) as "With Pathogenic allele", ClinVar (18x, pathogenic including review by expert panel ENIGMA), Clinvitae, COGR (3x, pathogenic), LOVD 3.0 (23x, affects function), BIC Database (29x, pathogenic), and ARUP Laboratories (pathogenic). The variant was also identified by our laboratory in 4 individuals with breast, ovarian, and pancreatic cancer. The variant was not found in Cosmic, MutDB, UMD-LSDB, or the Zhejiang University Database. The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.5073dupA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1692 and leads to a premature stop codon at position 1694. 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		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV000593745.1

#	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

From Department of Medical Genetics, Oslo University Hospital, SCV000605702.3

#	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 HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha, SCV000840551.1

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

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

From GenomeConnect, ClinGen, SCV001423223.1

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

Description

Variant interpretted as Pathogenic and reported on 08-30-2017 by Lab or GTR ID 505849. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

#	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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001434850.1

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

Description

The c.5073dupA (p.Trp1692Metfs*3) variant in the BRCA2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with breast cancer or ovarian cancer (PMID: 11179017, 14559878, 16683254, 26026974, 26641009). This variant has been seen 29 times in the Breast Cancer Information Core (BIC) dataset and is extremely rare in the general population according to the gnomAD. Therefore, this c.5073dupA (p.Trp1692Metfs*3) variant in the BRCA2 gene 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 Molecular Endocrinology Laboratory, Christian Medical College, SCV002004011.1

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

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512263.1

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

Description

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate

#	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 BRCAlab, Lund University, SCV004243650.1

#	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 All of Us Research Program, National Institutes of Health, SCV004845762.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	PubMed (23)

Description

This variant inserts 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 is also known as 5301insA, 5302insA, c.5066_5067insA and c.5073insA in the literature. This variant has been detected in over 20 individuals and families affected with breast, ovarian and fallopian tube cancer (PMID: 11179017, 11938448, 12181777, 14973102, 15131399, 16683254, 18819001, 19052777, 19796187, 21324516, 21465317, 23977390, 24333842, 24728189, 26026974, 26787237, 27741520, 28486781, 32022259, 33471991), an individual affected with pancreatic cancer (PMID: 25479140) and 2 unaffected carriers (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001899). This variant also has been observed with another pathogenic BRCA2 mutation in an individual affected with the recessive disease Fanconi anemia (PMID: 14559878). This variant has been identified in 4/230778 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		10	not provided	not provided	not provided

Last Updated: May 19, 2024

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