rs80359380

Positions:

• chr13-32337618-C-CT
• chr13-32337618-C-CTT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.3264dup​(p.Gln1089SerfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000503 in 1,590,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. P1088P) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:23 O:1
• Conservation: PhyloP100: 0.300

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]

ACMG classification

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	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	c.3264dup	p.Gln1089SerfsTer10	frameshift_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 32

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: 6 AN: 232856 Hom.: 0 AF XY: 0.0000238 AC XY: 3 AN XY: 125808

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: 7 AN: 1438046 Hom.: 0 Cov.: 33 AF XY: 0.00000421 AC XY: 3 AN XY: 713214

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: 1 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74310

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:23 Other:1

Revision: reviewed by expert panel

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

Splicing

Name	Calibrated prediction	Score	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

Other links and lift over

dbSNP: rs80359380; hg19: chr13-32911755;