NM_000059.4(BRCA2):c.9672dup (p.Tyr3225fs) AND not provided

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Nov 10, 2023
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:: RCV000372727.21

Allele description [Variation Report for NM_000059.4(BRCA2):c.9672dup (p.Tyr3225fs)]

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]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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BioProject Links for Protein (Select 491787735) (1)
BioProject
PREDICTED: Homo sapiens hexosaminidase D (HEXD), transcript variant X8, mRNA
PREDICTED: Homo sapiens hexosaminidase D (HEXD), transcript variant X8, mRNA
gi|2462554539|ref|XM_054315762.1|

Nucleotide
LINC02837 long intergenic non-protein coding RNA 2837 [Homo sapiens]
LINC02837 long intergenic non-protein coding RNA 2837 [Homo sapiens]
Gene ID:101928144

Gene
Gene Links for GEO Profiles (Select 77260162) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329588	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 31, 2022)	germline	clinical testing	Citation Link,
SCV000889186	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jun 17, 2022)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 22720145, 12065746, 24156927, 25103822, 32341426, 26740091, 25452441, 26467025
SCV001762267	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 17, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001905702	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
SCV001956712	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002035341	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV004563568	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Nov 10, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	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	clinical testing

Citations

PubMed

Diagnosis of fanconi anemia: mutation analysis by next-generation sequencing.

Ameziane N, Sie D, Dentro S, Ariyurek Y, Kerkhoven L, Joenje H, Dorsman JC, Ylstra B, Gille JJ, Sistermans EA, de Winter JP.

Anemia. 2012;2012:132856. doi: 10.1155/2012/132856. Epub 2012 Jun 3.

PubMed [citation]

PMID:: 22720145
PMCID:: PMC3374947

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

See all PubMed Citations (9)

Details of each submission

From GeneDx, SCV000329588.7

#	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 in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: cell line with this variant exhibited sensitivity to MMC exposure, increased IR induction of foci (present in both cytoplasm and nucleus) and absent FANCD2/BRCA2 complex in chromatin (Wang 2004); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants are considered pathogenic by a well-established clinical consortium and/or database.; Also known as c.9900dupA; This variant is associated with the following publications: (PMID: 24301060, 28152038, 24156927, 14559878, 16683254, 16115142, 25447315, 25452441, 15689453, 24312913, 11597388, 15645491, 22921157, 26846091, 26740091, 22720145, 29922827, 29446198, 29753700, 30720243, 30291343, 32341426, 30787465, 31076742, 35216584, 12065746, 15199141, 10733923, 9126738)

#	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, SCV000889186.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The BRCA2 c.9672dup (p.Tyr3225Ilefs*30) frameshift variant (also known as c.9672_9673insA and 9900insA) alters the translational reading frame of the BRCA2 mRNA and is predicted to cause the premature termination of BRCA2 protein synthesis. Although it is located in the last exon of BRCA2 and is not expected to undergo nonsense-mediated decay, the variant removes the last 194 residues of the BRCA2 protein including the RAD51-interaction region involved in recombination-mediated DNA repair (PMID: 17515903 (2007)). The frequency of this variant in the general population, 0.000004 (1/249592 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 32341426 (2020), 25452441 (2015), 25103822 (2014), 24156927 (2014)), as well as Fanconi anemia (PMIDs: 26740091 (2016), 22720145 (2012), 12065746 (2002)). 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 Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001762267.1

#	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 Laboratory, Department of Pathology, Netherlands Cancer Institute - VKGL Data-share Consensus, SCV001905702.1

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001956712.1

#	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 Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002035341.1

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004563568.1

#	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.9672dup; p.Tyr3225IlefsTer30 variant (rs80359773), also known as 9900insA, is reported in multiple individuals and families with hereditary breast and ovarian cancer syndrome and found compound heterozygous in at least one individual with Fanconi anemia (de Jonge 2019, Howlett 2002, Verhoog 2001). This variant is classified as pathogenic by an expert panel in the ClinVar Database (Variation ID: 126217). It is only found on one allele in the Genome Aggregation Database (v2.1.1), 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. This variant results in a premature termination codon in the last exon of the BRCA2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated BRCA2 protein. Based on available information, this variant is considered to be pathogenic. References: de Jonge MM et al. Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity. Clin Cancer Res. 2019 Dec 15;25(24):7517-7526. PMID: 31492746. Howlett NG et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002 Jul 26;297(5581):606-9. PMID: 12065746. Verhoog LC et al. Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families. Eur J Cancer. 2001 Nov;37(16):2082-90. PMID: 11597388.

#	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

Last Updated: May 12, 2024

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