rs80359499

Positions:

• chr13-32339592-C-CT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.5238dup​(p.Asn1747Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,548 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. S1746S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:35 O:1
• Conservation: PhyloP100: 0.0380

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32339592-C-CT is Pathogenic according to our data. Variant chr13-32339592-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 37954.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5238dup	p.Asn1747Ter	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5238dup	p.Asn1747Ter	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458548 Hom.: 0 Cov.: 43 AF XY: 0.00000276 AC XY: 2 AN XY: 725606

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:35 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2020	PVS1, PM2, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2021	Nonsense 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; Reported in association with hereditary breast and/or ovarian cancer (Frank 1998, Meindl 2002, Nanda 2005, Pohlreich 2005, van der Hout 2006, Song 2014, Wong-Brown 2015, Frey 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 24504028, 24728189, 26681312, 27856273, 28495237, 28324225, 32295079, 16168118, 18703817, 22430266, 16234499, 15131399, 16683254, 9667259, 23110154, 27157322, 25682074, 11802209, 28454591, 27930734, 26022348, 30702160, 32719484) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 16, 2021	This frameshift variant causes the premature termination of BRCA2 protein synthesis. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In addition, it has been described in individuals with breast cancer and ovarian cancer (PMID: 26681312 (2015), 25682074 (2015), 25186627 (2015), 24728189 (2014), 22430266 (2012)). Based on the available information, this variant is classified as pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:9 Other:1

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, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	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 has been reported in at least eight individuals affected with breast or ovarian cancer and additional suspected hereditary breast and ovarian cancer families (PMID: 9667259, 11802209, 16168118, 16234499, 18703817, 23110154, 24504028, 24728189, 25186627, 25682074, 26681312). This variant has not been identified 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	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Aug 01, 2024	- -
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	Sharing Clinical Reports Project (SCRP)	May 06, 2011	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1; PM2_supporting; PM5_PTC_Strong -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2015	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2022	Variant summary: BRCA2 c.5238dupT (p.Asn1747X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 252034 control chromosomes. c.5238dupT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Meindl_2002, Nanda_2005, Palma_2008, Pern_2012, Pohlreich_2005, Song_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 06, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Asn1747*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11802209, 16168118, 23110154, 25682074, 26681312). This variant is also known as 5466insT. ClinVar contains an entry for this variant (Variation ID: 37954). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 28, 2021	The c.5238dupT pathogenic mutation (also known as p.N1747*), located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 5238. This changes the amino acid from a asparagine to a stop codon within coding exon 10. This mutation has been described in multiple breast and/or ovarian cancer families, including individuals with pre-menopausal and triple negative breast cancer (Frank TS et al. J. Clin. Oncol. 1998 Jul;16(7):2417-25; Meindl A et al. Int. J. Cancer. 2002 Feb;97(4):472-80; Pohlreich P et al. Breast Cancer Res. 2005 Jul;7(5):R728-36; Palma MD et al. Cancer Res. 2008 Sep;68(17):7006-14; Pern F et al. PLoS One. 2012 Oct;7(10):e47993; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Schroeder C et al. Breast Cancer Res. Treat. 2015 Jul;152:129-136). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as 5466insT 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	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 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 expected to result in an absent or non-functional protein product. This variant has been reported in at least eight individuals affected with breast or ovarian cancer and additional suspected hereditary breast and ovarian cancer families (PMID: 9667259, 11802209, 16168118, 16234499, 18703817, 23110154, 24504028, 24728189, 25186627, 25682074, 26681312). This variant has not been identified 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. -

Breast and/or ovarian cancer Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	CZECANCA consortium	Jun 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 17, 2021	- -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

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

Feb 16, 2022

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Feb 14, 2024

Criteria applied: PVS1,PM5_STR,PM2_SUP -

BRCA2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

The BRCA2 c.5238dupT variant is predicted to result in premature protein termination (p.Asn1747*). This variant has been documented to be pathogenic in multiple unrelated individuals with breast or ovarian cancer [Reported in Table III as 5466insT(1747X) in Meindl et al. 2002. PubMed ID: 11802209; reported as c.5238insT in Pern et al. 2012. PubMed ID: 23110154; reported in Table S1 as S1746fs in Cunningham et al. 2014. PubMed ID: 24504028; reported in Suppl Table 1 as c.5237_5238insT (p.S1746fs) in Schroeder et al. 2015. PubMed ID: 26022348]. This variant has not been reported in a large population database, indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37954/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Asn1747X variant was identified in 3 of 1936 proband chromosomes (frequency: 0.002) from German and Czech individuals or families with breast/ovarian or triple negative breast cancers (Meindl 2002, Pohlreich 2005, Pern 2012). The variant was also identified in dbSNP (ID: rs80359499) “With Pathogenic allele”, but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. The variant was identified in HGMD, the BIC database (9X with pathogenic clinical importance), and in Clinvitae (3x), the ClinVar database by multiple submitters (the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) as a pathogenic variant, 2X by BIC (both somatic and germline) classification not provided, Invitae, classification not provided, classified as pathogenic by Ambry Genetics, GeneDX and Molecular Diagnostic Laboratory - CHEO ). The c.5238 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1747 and leads to a premature stop codon at position 1747. 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 laboratory’s criteria to be classified as pathogenic. -

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: rs80359499; hg19: chr13-32913729;