Variant 13-32337618-C-CT details in Genebe, Genetics Data Aggregator

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 13-32337618-C-CT is Pathogenic according to our data. Variant chr13-32337618-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 37830.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.3264dup	p.Gln1089SerfsTer10	frameshift_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.3264dup	p.Gln1089SerfsTer10	frameshift_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000258

AC:

AN:

232856

Hom.:

AF XY:

0.0000238

AC XY:

AN XY:

125808

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000196

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000487

AC:

AN:

1438046

Hom.:

Cov.:

AF XY:

0.00000421

AC XY:

AN XY:

713214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000149

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.08e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 06, 2023	This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3492insT, 3492dupT, 3492_3493insT and c.3264_3265insT in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least ten individuals affected with breast, ovarian and uterine cancer (PMID: 11843247, 12655567, 12845657, 12955716, 20104584, 30630528, 33471991; Leiden Open Variation Database DB-ID BRCA2_000667; Color internal data) and two individuals affected with pancreatic cancer (PMID: 29506128, 30274973) and is a recurrent mutation detected in suspected hereditary breast and ovarian cancer families of Latin American, Caribbean and Spanish origins (PMID: 19241424, 19941167, 20033483, 23233716, 23479189). This variant also has been detected in trans with two different BRCA2 pathogenic mutations in two individuals who had clinical features consistent with Fanconi anemia (PMID: 23613520, 29753700). This variant has been identified in 6/232856 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 27, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Mar 07, 2020	This variant inserts a single nucleotide causing a frameshift at position 1089 which leads to a premature stop codon. This variant is predicted to result in a loss of protein function, which is a well-established mechanism of disease for the BRCA2 gene (Borg 2010). This variant has been observed in many families with breast and/or ovarian cancer, especially families with Spanish ancestry (Diez 2010, de Sanjose 2003, Esteban Cardenosa 2010, Weitzel 2005), and in an individual with Fanconi anemia (Chandrasekharappa 2013). Based on this information, we consider this variant to be pathogenic. PS4-moderate; PVS1 -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 11, 2014	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 17, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 03, 2023	PP5, PM3, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 30, 2019	The BRCA2 c.3264dup (p.Gln1089Serfs*10) variant (also known as 3492insT) alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.0002 (6/30610 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in affected individuals with breast and/or ovarian cancer, pancreatic ductal adenocarcinoma, and medulloblastoma (PMIDs: 20104584 (2010), 29506128 (2018), 29753700 (2018), 30274973 (2018), and 30630528 (2019)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2023	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 the heterozygous state in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 19941167, 20033483, 23479189, 23233716, 28477318, 29506128); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3492dupT; This variant is associated with the following publications: (PMID: 12955716, 20033483, 19941167, 23233716, 24259538, 23613520, 23479189, 12845657, 29907814, 30630528, 30720243, 34413315, 29922827, 28888541, 33858029, 18176857, 22426013, 11857748, 16758124, 26026974, 12655567, 19530235, 25371446, 25628955, 27842325, 26681312, 24123850, 28477318, 28985766, 28680148, 28127413, 29387975, 11802208, 29506128, 21548014, 30274973, 30322717, 31447099, 31589614, 32719484, 30787465, 30625039, 35264596, 29753700, 35451682) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	BRCA2: PVS1, PM2 -

Hereditary breast ovarian cancer syndrome

Pathogenic:4

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2016	Variant summary: The BRCA2 c.3264dupT (p.Gln1089Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not found in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals by publications. Multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Gln1089Serfs*10) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs777107618, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer and Fanconi anemia (PMID: 12845657, 16030099, 19941167, 20033483, 22426013, 23613520, 24123850, 25136594). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Spanish and American individuals of Latin American descent ancestry (PMID: 16030099, 19941167). This variant is also known as 3492insT and 3492_3493insT. ClinVar contains an entry for this variant (Variation ID: 37830). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2022	This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3492insT, 3492dupT, 3492_3493insT and c.3264_3265insT in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least ten individuals affected with breast, ovarian and uterine cancer (PMID: 11843247, 12655567, 12845657, 12955716, 20104584, 30630528, 33471991; Leiden Open Variation Database DB-ID BRCA2_000667; Color internal data) and two individuals affected with pancreatic cancer (PMID: 29506128, 30274973) and is a recurrent mutation detected in suspected hereditary breast and ovarian cancer families of Latin American, Caribbean and Spanish origins (PMID: 19241424, 19941167, 20033483, 23233716, 23479189). This variant also has been detected in trans with two different BRCA2 pathogenic mutations in two individuals who had clinical features consistent with Fanconi anemia (PMID: 23613520, 29753700). This variant has been identified in 6/232856 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 06, 2022	The c.3264dupT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 3264, causing a translational frameshift with a predicted alternate stop codon (p.Q1089Sfs*10). This alteration has been reported as a pathogenic mutation in numerous Spanish and Mexican breast and/or ovarian cancer kindreds (Llort G et al. Hum. Mutat. 2002 Mar;19:307; Weitzel JN et al. J. Clin. Oncol. 2013 Jan;31:210-6; Susswein LR et al. Genet Med. 2016 Aug;18(8):823-832; Gabaldo Barrios X et al. Fam. Cancer. 2017 Oct;16(4):477-489). This alteration has also been observed in Fanconi anemia patients (Myers K et al. Pediatr. Blood Cancer. 2012 Mar;58:462-5; Chandrasekharappa SC et al. Blood 2013 May;121:e138-48) and in a patient with pancreatic cancer (Lowery MA et al. J. Natl. Cancer Inst. 2018 Oct;110(10):1067-1074). Of note, this alteration is also designated as 3492insT in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jan 11, 2021	- -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 24, 2021

- -

Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 20, 2024

- -

Ovarian neoplasm

Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpreted as Pathogenic and reported on 02-02-2021 by Lab or GTR ID 500110. 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. -

Computational scores

Source: dbNSFP v4.3

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Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

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Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

13-32337618-C-CT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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