NM_000059.4(BRCA2):c.9672dup (p.Tyr3225fs) AND Breast-ovarian cancer, familial, susceptibility to, 2

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

Germline classification:: Pathogenic (9 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:: RCV000114151.19

Allele description

NM_000059.4(BRCA2):c.9672dup (p.Tyr3225fs)

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.9672dup (p.Tyr3225fs)

Other names:

9900insA; p.Tyr3225IlefsX30

HGVS:

NC_000013.10:g.32972321_32972322insA
NC_000013.11:g.32398185dup
NG_012772.3:g.87706dup
NM_000059.4:c.9672dupMANE SELECT
NP_000050.3:p.Tyr3225fs
LRG_293:g.87706dup
NC_000013.10:g.32972321_32972322insA
NC_000013.10:g.32972322_32972323insA
NC_000013.10:g.32972322dup
NC_000013.10:g.32972322dup
NM_000059.3:c.9672dupA
NM_000059.4:c.9672dup
U43746.1:n.9900_9901insA
p.Y3225Ifs*30

Protein change:

Y3225fs

Links:

Breast Cancer Information Core (BIC) (BRCA2): 9900&base_change=ins A; OMIM: 600185.0019; dbSNP: rs80359773

NCBI 1000 Genomes Browser:

rs80359773

Molecular consequence:

NM_000059.4:c.9672dup - 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

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Arabidopsis lyrata strain:MN47
Arabidopsis lyrata strain:MN47
Arabidopsis lyrata strain:MN47 Transcriptome or Gene expression

BioProject
COMM domain-containing protein 7 isoform X1 [Homo sapiens]
COMM domain-containing protein 7 isoform X1 [Homo sapiens]
gi|530417875|ref|XP_005260356.1|

Protein
Related DataSets for GEO DataSets (Select 5674) (51)
GEO DataSets
GEO Profiles Links for Nucleotide (Select 46249766) (149)
GEO Profiles
Nucleotide Links for Protein (Select 2217302994) (2)
Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000147696	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Pathogenic (May 29, 2002)	germline	clinical testing
SCV000196029	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]
SCV000301407	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,
SCV000328160	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,
SCV000733341	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV000743528	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Oct 10, 2014)	germline	clinical testing	Citation Link,
SCV000744792	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,
SCV002581551	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004846215	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Feb 24, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 12065746, 16683254, 16920162, 17515903, 22720145, 24156927, 25452441, 26740091, 27153395, 25741868

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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	31	not provided	108544	not provided	clinical testing, curation
Caucasian	germline	yes	1	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

Citations

PubMed

Biallelic inactivation of BRCA2 in Fanconi anemia.

Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D'Andrea AD.

Science. 2002 Jul 26;297(5581):606-9. Epub 2002 Jun 13.

PubMed [citation]

PMID:: 12065746

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 (10)

Details of each submission

From Breast Cancer Information Core (BIC) (BRCA2), SCV000147696.1

#	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	Caucasian	1	not provided	not provided	clinical testing	not provided
4	Central/Eastern European	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		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		1	not provided	not provided	not provided

From Michigan Medical Genetics Laboratories, University of Michigan, SCV000196029.1

#	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 Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), SCV000301407.2

#	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, SCV000328160.4

#	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	31	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV000733341.1

#	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 Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV000743528.1

#	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, SCV000744792.1

#	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 MGZ Medical Genetics Center, SCV002581551.1

#	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, SCV004846215.1

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

Description

This variant inserts 1 nucleotide in codon 3225 in exon 27 of the BRCA2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is also known as 9900insA and c.9672_9673insA in the literature. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. This variant is expected to disrupt the RAD51 binding domain that has been reported to be essential for homologous recombination and DNA repair (PMID: 17515903). Cell lines that are compound heterozygous for this variant and a known pathogenic BRCA2 truncation variant produced a truncated protein consistent with truncation in exon 27 (PMID: 12065746) and exhibited hypersensitivity to mitomycin C and other DNA damaging agents (PMID: 12065746, 16920162). This variant also has been reported in multiple individuals with personal or family history of breast and/or ovarian cancer (PMID: 16683254, 24156927, 25452441, 27153395, Color internal data). This variant has also been reported in three individuals who are compound heterozygous with a pathogenic BRCA2 covariant and affected with Fanconi anemia (PMID: 12065746, 22720145, 26740091). An external laboratory has reported the associated cancer histories of multiple carriers of this variant are inconsistent with known BRCA2 pathogenic variants (https://myriad-web.s3.amazonaws.com/publications/74925948-ACMG%202017%20Mundt%20variant%20classification%20Presented.pdf). This variant has been identified in 1/249592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this rare variant has been observed in multiple individuals and families affected with BRCA2-related phenotypes. Although additional studies are necessary to determine the role of this variant in disease and penetrance conclusively, this variant is classified as Likely Pathogenic based on the available evidence.

#	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: May 1, 2024

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